Novel 4-(2-furoyl) aminopiperidienes, intermediates for synthesizing the same, processes for preparing the same and medicinal use of the same

ABSTRACT

A compound represented the general formula (V): 
     
       
         
         
             
             
         
       
     
     wherein
 
X is CH or N; and
 
Y a  is a group of the general formula selected from:

CROSS-REFERENCED APPLICATION

This application is a Divisional Application of U.S. patent applicationSer. No. 10/492,065, filed on Oct. 20, 2004, which is incorporatedherein in its entirety by reference.

TECHNICAL FIELD

This invention relates to novel 4-(2-furoyl)aminopiperidines andprocesses for preparing them, intermediates for synthesizing them andprocesses for preparing them, and their in vivo metabolites, as well asto medicaments containing them, more specifically, their use as opioid μantagonists.

BACKGROUND ART

Opioid receptors are the receptors to which drugs having morphine-likeaction specifically bind, and they are found in the central nervoussystem or intestinal nervous system. Opioid receptors are known toinclude the three types of μ, δ and κ, where the primary structure ofeach receptor has been elucidated by cDNA cloning (Wang J-B, FEBS Lett,338: 217-222, 1994, Simonin F, Mol Pharmacol, 46: 1015-1021, 1994,Simonin F, Proc Natl Acad Sci USA, 92: 7006-7010, 1995). Pharmacologicalactivities of these opioid receptors differ, depending on the types ofreceptors (Martin W R, J Pharmacol Exp Ther. 197: 517-532, 1976). The μreceptors are involved in analgesia, respiratory depression, euphoria,psychosomatic dependence, tolerance, enterokinesis depression,bradycardia, constipation, miosis, etc. On the other hand, the δreceptors are involved in analgesia, psychosomatic dependence, emotionalreaction, etc. The κ receptors are involved in analgesia, sedation,euphoria, diuresis, aversions miosis, etc.

Morphine is a representative μ receptor agonist (Wood P L,Neuropharmacology, 20: 1215-1220, 1981) and it has been used for thosepatients with carcinomatous pain or postoperative pain as a potentanalgesic. However, morphine exerts analgesic activity, while it causesside effects such as constipation, nausea/emesis, drowsiness,hallucination/obfuscation, respiratory depression, xerostomia/mouthdryness, perspiration, itch, dysuria, unsteadiness/dizziness, andmyoclonus. Of these side effects, constipation, nausea/emesis mayfrequently appear, and itch is also very frequently observed inintrathecal or epidual administration (Guidelines for Alleviation ofCarcinomatous Pain, Ed. by the Alleviation Medical Society of Japan,“the Committee for Drafting Guidelines for Alleviation CarcinomatousPain”, Department of Publication of Medical Books, SINKO-SYUPPAN KOUEKICo., Ltd., 68-78, 2000).

Opioid peptide is a generic name for the peptide group havingmorphine-like action and binding to opioid receptors, and the opioidpeptides found in the central nervous system and peripheral tissues(intestine, adrenal gland, etc.) are referred to as “endogenous opioidpeptides.” β-Endorphin, enkephalin and dynorphin are known as endogenousopioid peptides. Of these peptides, β-endorphin and enkephalin haveaffinity to μ receptors (Opioid Peptides, Ed. by Hiroo IMURA, CHYUGAIIGAKU Co., Ltd., 240-250, 1985). It has also been reported thatproduction and release of these endogenous opioid peptides arestimulated under various stress environments (in Enkephalins andEndoephins, Ed. by Plotnikoff N P, Plenum, 1986). This has pointed outthat endogenous opioid peptides may be a pathogenic cause of idiopathicconstipation, postoperative ileus, paralytic ileus, irritable bowelsyndrome, chronic pruritus, etc. (Orwoll E S, Endocrinology, 107:438-442, 1980, Konturek S J, Am J Physiol, 238: G384-G389, 1980,Yamaguchi T, Jpn J Phammacol, 78: 337-343, 1998).

It is, therefore, believed that the μ receptor antagonists are effectiveagainst side effects which are caused by the u receptor agonists, suchas constipation, nausea/emesis, and itch, or diseases such as idiopathicconstipation, postoperative ileus, paralytic ileus, irritable bowelsyndrome and chronic pruritus.

According to Japanese Patent Kokai No. 264460/1988 (JP-A-63264460), adrug having the action of reversing respiratory depression, one of sideeffects of morphine, that is, an opioid μ receptor antagonist has beenidentified as the compound of the formula (XI), which is an analogouscompound originated from fentanyl, an opioid μ receptor agonist.

However, the opioid μ receptor antagonistic activity of this drug isweak and insufficient as a therapeutic agent for imperfect enterokinesissuch as constipation and irritable bowel syndrome. Therefore, there hasbeen a need for more potent opioid μ receptor antagonists.

DISCLOSURE OF THE INVENTION

The present inventors conducted thorough investigations to solve theabove problems and, as a result, have found that compounds of thegeneral formula (I) or pharmaceutically acceptable salts thereof asdescribed below possess potent opioid μ receptor antagonistic activity.The present compounds correspond to compounds of the formula (XI)wherein the 4-methylpyridin-2-yl group has been structurally convertedto a 5-methylpyridin-2-yl group or a p-tolyl group and a cycloalkylgroup is bound to the piperidine group at the 1-position thereof via asuitable spacer moiety and the compounds of the formula (XI) areanalogous to fentanyl as disclosed in Japan Kokai 284460/1988.

wherein

X is CH or N; and

Y is a group of the general formula (II):

or a group of the general formula (II-a):

or a group of the general formula (III):

whereina, b and c are each an integer of 0-6;

Z is CH₂ or NH; W is O or S;

T is O or N—R¹⁵ R¹⁵ is H, a C1-C6 alkyl group,a benzyl group or a phenethyl group;R¹ is H, a C1-C6 alkoxycarbonyl group, a benzyloxycarbonyl group, acarboxy group, a 2-phenyl-1,3-dioxan-5-yl group, a2,2-dimethyl-1,3-dioxan-5-yl group,or a group of the general formula (IV):

whereind is an integer of 0-6; andR³, R⁴, and R⁵ may be the same or different and are each independentlyH, —(CH₂)_(e)R⁶ or —(CH₂)_(f)CONR⁷R⁸ wherein e and f are each an integerof 0-6; R⁶ is a hydroxy group, a C1-C6 alkanoyloxy group, a benzoyloxygroup, a 2-furoyloxy group, a C1-C6 alkoxy C1-C6 alkoxy group, a C1-C6alkoxycarbonylphenoxy group, a carboxyphenoxy group, a dicarboxyphenoxygroup, a di C1-C6 alkoxycarbonylphenoxy group, a dihydroxy C1-C6alkylphenoxy group, an amino group, a C1-C6 alkoxycarbonylamino group, aC1-C6 alkyl sulfonamido group, a benzenesulfonamido group, ap-toluenesulfonamido group, a p-halobenzenesulfonamido group, a carboxygroup, a C1-C6 alkoxycarbonyl group, a carbohydroxamic acid group, acarbohydroxamic acid C1-C6 alkyl ester group, a cyano group, a1H-tetrazol-5-yl group, a 1-(C1-C6 alkyl)-1H-tetrazol-5-yl group, a2-(C1-C6 alkyl)-2H-tetrazol-5-yl group, a N²-hydroxycarbamidoyl group, aN′-(C1-C6 alkoxycarbonyl)-N²-hydroxycarbamidoyl group, a2H-5-thioxo-1,2,4-oxadiazol-3-yl group, a 2H-5-oxo-1,2,4-oxadiazol-3-ylgroup, a guanidino group, a di C1-C6 alkoxycarbonyl-guanidino group or amorpholinocarbonyl group; andR⁷ and R⁸ may be the same or different and are each independently is H,a C1-C6 alkyl group, a C1-C6 alkanoyloxy C1-C6 alkyl group, a hydroxyC1-C6 alkyl group, a bis(C1-C6 alkanoyloxy C1-C6 alkyl)methyl group, abis(hydroxy C1-C6 alkyl)methyl group, a tris(C1-C6 alkanoyloxy C6alkyl)methyl group, a tris(hydroxy C1-C6 alkyl)methyl group, a carboxyC1-C6 alkyl group, a C1-C6 alkoxycarbonyl C1-C6 alkyl group, aN,N-bis(C1-C6 alkanoyloxy C1-C6 alkyl)carbamoyl C1-C6 alkyl group, aN,N-bis(carboxy C1-C6 alkyl)carbamoyl C1-C6 alkyl group, a C1-C6alkylsulfonyl group, a carboxyphenyl group or a pyrazinyl group; andR² is H or a group of the above general formula (IV).

Moreover, it has also been found that the group of the present compoundspossess peripheral selectivity and are medicaments with less activity tothe central nervous system and high selectivity to digestive tracts.Therefore, the 4-(2-furoyl)aminopiperidines according to this inventionare believed to be effective against side effects which are caused bythe μ receptor agonists such as constipation, nausea/emesis, and itch ordiseases such as idiopathic constipation, postoperative ileus, paralyticileus, irritable bowel syndrome and chronic pruritus.

In the compounds represented by the general formula (I), the substituentY bears a group selected from a cycloalkyl group, a piperidyl group or atetrahydropyranyl group, as shown in the general formulae (II), (II-a)and (III). In the general formulae (II) and (III), b is an integer of0-6, so that specific examples of the cycloalkyl group may includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl and cyclononyl groups.

The cycloalkyl group, the piperidyl group or the tetrahydropyranyl groupis bound to the piperidyl group of the compound represented by thegeneral formula (I) via

the structure as shown by the general formulae (II), (II-a) and (III).The cycloalkyl group, the piperidyl group or the tetrahydropyranyl groupbears a substituent as defined by R¹.

Specific examples of R¹ may include hydrogen, a carboxy group, acarboxymethyl group, a 3-carboxypropyl group, a 3,3-bis(carboxy)propylgroup, a N,N-bis(carboxymethyl)carba-moylmethyl group, aN-(carboxymethyl)carbamoylmethyl group, aN-(2-carboxyethyl)carbamoylmethyl group, aN,N-bis[N,N-bis-(carboxymethyl)carbamoylmethyl]carbamoylmethyl, amethoxy-carbonyl group, a methoxycarbonylmethyl group, a3-methoxy-carbonylpropyl group, a 3,3-bis(methoxycarbonyl)propyl group,a 3,3,3-tris(ethoxycarbonyl)propyl group, aN,N-bis(ethoxycarbonylmethyl)carbamoylmethyl group, aN-(ethoxycarbonylmethyl)carbamoylmethyl group, aN-(2-ethoxycarbonylethyl)-carbamoylmethyl group, aN-(3-ethoxycarbonylpropyl)carbamoyl-methyl group, a N,N-bis[N,N-

bis(ethoxycarboxymethyl)carbamoylmethyl]carbamoylmethyl group, a2-hydroxyethyl group, a 3-hydroxypropyl group, a3,3-bis(hydroxymethyl)propyl group, a5-hydroxy-3,3-bis(hydroxymethyl)pentyl group, a 1,3-dihydroxy-2-propylgroup, a 6-carboxy-3,3-bis(hydroxy-methyl) hexyl group, a6-methoxycarbonyl-3,3-bis(hydroxy-methyl)hexyl group, atris(hydroxymethyl)methylcarbamoylmethyl group, aN,N-bis[tris(hydroxymethyl)methylcarbamoylmethyl]-carbamoylmethyl group,a 3-acetoxypropyl group, a 3,3-bis-(acetoxymethyl)propyl group, a3,3-bis(methoxymethoxymethyl)-propyl group, a5-acetoxy-3,3-bis(acetoxymethyl)pentyl group, a 2-phenyl-1,3-

2,2-dimethyl-1,3-dioxan-5-yl group, a6-methoxycarbonyl-3,3-bis(benzoyloxymethyl)hexyl group, a2-(2-furoyloxy)ethyl group, a tris(acetoxymethyl)-methylcarbamoylmethylgroup, a carbamoylmethyl group, a

cyanomethyl group, a 2-cyanoethyl group, a 2-(tetrazolyl)ethyl group, anacetohydroxamic acid group, a N-(t-butoxy)carbamoyl-methyl group, a2-aminoethyl group, a 2-(t-butoxycarboxamido)-ethyl group, a2-(methanesulfonamido)ethyl group, a2-(p-chloro-benzenesulfonamido)ethyl group, a2-(2-methoxycarbonyl-phenoxy)ethyl group, a 2-(2-carboxyphenoxy)ethylgroup, a 2-(3,5-dicarboxyphenoxy)ethyl group, a2-(3,5-dimethoxy-carbonylphenoxy)ethyl group, a2-(3,5-dihydroxymethylphenoxy)-ethyl group, a2-(1-methyl-1H-tetrazol-5-yl)ethyl group, a2-(2-methyl-2H-tetrazol-5-yl)ethyl group, a2-(N¹-methoxy-carbonyl-N²-hydroxycarbamidoyl)ethyl group, a2-(1,2-di-methoxycarbonylguanidino)ethyl group, amethanesulfonylcarba-moylmethyl group, a carboxyphenylcarbamoylmethylgroup, a pyrazinylcarbamoyl methyl group, etc.

Specific examples of —(CH₂)_(a)— in the group of the general formula(II) may include a single bond, a methylene group, an ethylene group, atrimethylene group, a tetramethylene group, a pentamethylene group, ahexamethylene group, etc.

Specific examples of the group of the general formula (II-a) may includea 2-[4-(2-hydroxyethyl)tetrahydropyran-4-yl]ethyl group, a2-[1-benzyl-4-(2-hydroxyethyl)piperidin-4-yl]ethyl group, etc.

Specific examples of the group of the general formula (III) may includea 2-(cyclohexylacetamido)benzyl group, a2-[2-(cyclohexylacetamido)phenyl]ethyl group, a2-[2-[N-(cy-clohexylacetyl)carboxymethylamino]phenyl]ethyl group, a2-[2-[N-(cyclohexylacetyl)-tert-butoxycarbonylmethylamino]phenyl]ethylgroup, a 3-[2-(cyclohexylacetamido)phenyl]propyl group, a3-[2-(3-cyclohexylpropionamido)phenyl]propyl group, a3-[2-[N-(3-cyclohexylpropionyl)carboxymethylamino]phenyl]propyl group, a3-[2-[N-(3-cyclohexylpropionyl)-tert-butoxycarboxy-methylamino]phenyl]propylgroup, a3-[2-[N-(3-cyclohexylpro-pionyl)-3-carboxypropylamino]phenyl]propylgroup, a 2-[2-(3-cyclohexylureido)phenyl]ethyl group, a2-[2-[N—(N-cyclohexylcarbamoyl)carboxymethylamino]phenyl]ethyl group, a2-[2-[N—(N-cyclohexylcarbamoyl)ethoxycarbonylmethylamino]phenyl]ethylgroup, a 3-[2-(4-cyclohexylbutyramido)phenyl]propyl group, a2-[2-[N-[1-(carboxymethyl)cyclohexylacetyl]carbonylmethylamino]phenyl]ethylgroup, a2-[2-[N-[1-(carboxymethyl)cyclohexyl-acetyl]ethoxycarbonylmethylamino]phenyl]ethylgroup, a 2-[2-[1-(carboxymethyl)cyclohexylacetamido]phenyl]ethyl group,a 2-[2-[1-(methoxycarboxymethyl)cyclohexylacetamido]phenyl]-ethyl group,a 3-[2-(3-cyclohexylureido)phenyl]propyl group, a3-[2-[N-(3-cyclohexylthioureido)phenyl]propyl group, etc.

A compound of this invention represented by the general formula (X):

wherein

X is CH or N; and

Y_(a) is a group of the general formula (VI):

or a group of the general formula (VI-a):

or a group of the general formula (VII):

or a group of the general formula (VIII):

whereina, b and c are each an integer of 0-6;

Z is CH₂ or NH; W is O or S;

T is O or N—R¹⁵ wherein R¹⁵ is H, a C1-C6 alkyl group, a benzyl group ora phenethyl group;R⁹ is H, a C1-C6 alkoxycarbonyl group, a benzyloxycarbonyl group, acarboxy group, a 2-phenyl-1,3-dioxan-5-yl group, a2,2-dimethyl-1,3-dioxan-5-yl group or a group of the general formula(IX):

whereind is an integer of 0-6; and R¹¹, R², and R¹³ may be the same ordifferent and are each independently H or —(CH₂)_(e)R¹⁴ wherein e is0-6; R¹⁴ is a C1-C6 alkanoyloxy group, a benzoyloxy group, a 2-furoyloxygroup, a C1-C6 alkoxy C1-C6 alkoxy group, a C1-C6 alkoxycarbonylphenoxygroup, a di C1-C6 alkoxycarbonylphenoxy group, a dihydroxy C1-C6alkylphenoxy group, a carboxy group, a C1-C6 alkoxycarbonyl group, aC1-C6 alkoxycarbonylamino group, a benzyloxycarbonyl group, a cyanogroup or a C1-C6 alkylsulfonamido group; andR¹⁰ is H or a group of the general formula (IX), may be prepared, forexample, by reacting a compound represented by the general formula (V):

wherein X and Ya are the same as those defined in the general formula(X), with 2-furancarboxylic acid or its reactive derivative such as2-furoyl chloride.

The reaction is carried out in an organic solvent such asdichloromethane, chloroform, diethyl ether or tetrahydrofuran at atemperature of from ice cooling temperature to reflux temperature.

When the reaction with 2-furoyl chloride is carried out in the presenceof a base, specific examples of the base may include triethylamine andthe like.

Specific examples of the compound represented by the general formula (X)may include:

-   N-[1-(cyclohexylmethyl)piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   N-[1-(2-cyclohexylethyl)piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   N-[1-(3-cyclohexylpropyl)piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   N-[1-(4-cyclohexylbutyl)piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   N-[1-(2-cyclohexyloctylethyl)piperidin-4-yl]-N-(5-methylpyr-din-2-yl)-2-furancarboxamide,-   N-[1-(3-cyclohexylpropyl)piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-(1-cyclohexylpiperidin-4-yl)-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   N-[1-[3-[2-(cyclohexylacetamido)phenyl]propyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   N-[1-[2-[2-(cyclohexylacetamido)phenyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   methyl    [1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxami-do]piperidin-1-yl]ethyl]cyclohexyl]acetate,-   methyl    [1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxami-do]piperidin-1-yl]ethyl]cyclopentyl]acetate,-   methyl    [1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxami-do]piperidin-1-yl]ethyl]cyclohexanecarboxylate,-   [2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexanecarboxylic    acid,-   methyl    4-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxa-mido]piperidin-1-yl]ethyl]cyclohexyl]butyrate,-   triethyl    3-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarbox-amido]piperidin-1-yl]ethyl]cyclohexyl]-1,1,1-propanetricarboxylate,-   dimethyl    3-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperi-din-1-yl]ethyl]cyclohexyl]-1,1-propanedicarboxylate,-   methyl    [1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetate,-   propyl    3-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarbox-amido]piperidin-1-yl]methyl]cyclohexyl]acetate,-   2-[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,3-diacetoxypropane,-   N-[1-[2-[1-(4-methoxymethoxy)-3-(methoxymethoxy)butyl]cyclo-hexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   2-(acetoxymethyl)-2-[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane,-   N-[1-[2-[1-(2-phenyl-1,3-dioxan-5-yl)cyclohexyl]ethyl]piperidin-4-yl]-N-(-methylpyridin-2-yl)-2-furancarboxamide,-   N-[1-[2-[1-(2,2-dimethyl-1,3-dioxan-5-yl)cyclohexyl]ethyl]-piperidin-4]-yl]-N-(p-tolyl)-2-furancarboxamide,-   methyl    5,5-bis(benzoyloxymethyl)-7-[1-[2-[4-[N-(5-methylpyr-idin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]heptanoate,-   methyl    5,5-bis(benzoyloxymethyl)-7-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]heptanoate,-   2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,3-diacetoxypropane,-   2-[2-[1-[2-[4-[N-(5-methylpiperidin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethyl    2-furancarboxylate-   N-[1-[2-[1-(2-cyanoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   tert-butyl    [2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancar-boxamido]piperidin-1-yl]ethyl]cyclohexyl]ethyl]carbamate,-   N-[1-[2-[1-(2-methanesulfonamidoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   N-[1-[2-(cyclohexylacetamido)benzyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   N-[1-[2-[2-(cyclohexylacetamido)phenyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[3-[2-(3-cyclohexylpropionamido)phenyl]propyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   tert-butyl    [2-[3-[4-[N-(5-methylpyridin-2-yl)-2-furancarbox-amido]piperidin-1-yl]propyl]phenyl]carbamate,-   tert-butyl    [2-[3-[4-[N-(p-tolyl)-2-furancarboxamido]piperi-din-1-yl]propyl]phenyl]carbamate,-   N-[1-[2-[1-(2-cyanoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   2-(acetoxymethyl)-2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxa-mido]piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane,-   tert-butyl    2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]pipe-ridin-1-yl]ethyl]cyclohexyl]ethylcarbamate,-   dimethyl    5-[2-[1-[4-[N-(p-tolyl)-2-furancarboxamido]piperi-din-1-yl]ethyl]cyclohexyl]ethoxy]isophthalate,-   methyl    2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperi-din-1-yl]ethyl]cyclohexyl]ethoxy]benzoate,-   2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]ethyl    2-furancarboxylate-   methyl    4-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperi-din-]-yl]ethyl]cyclohexyl]butyrate,-   triethyl    3-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperi-din-1-yl]ethyl]cyclohexyl]-1,1,1-propanetricarboxylate,    etc.

A compound of the following general formula (XII):

wherein

X is CH or N; and

Yb is a group of the general formula (II):

wherein b is an integer of 0-6; andR¹ is a carboxy group or a group of the general formula (IV):

whereind is an integer of 0-6; R³ is H or —(CH₂)_(e)COOH; R⁴ and R⁵ may be thesame or different and are each independently H or —(CH₂)_(e)R⁶ wherein eis an integer of 0-6; R⁶ is a carboxy group, a hydroxy group, or acarboxyphenoxy group,which is included within the compounds of this invention represented bythe general formula (I), may be prepared by hydrolysis of thecorresponding methyl ester, ethyl ester, etc. with a base (e.g., lithiumhydroxide, sodium hydroxide, potassium hydroxide or potassium carbonate)or by debenzylation of the corresponding benzyl ester in the presence ofa catalyst (e.g., palladium-carbon) under hydrogen atmosphere.

The reaction is carried out in water or an organic solvent such asmethanol, ethanol, 1,4-dioxane, acetic acid, or ethyl acetate at atemperature of from room temperature to reflux temperature.

Specific examples of the compound represented by the general formula(XII) may include:

-   [1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetic    acid,-   [1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclopentyl]acetic    acid,-   4-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]butyric    acid,-   3-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]-1,1-propanedicarboxylic    acid,-   3-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]-1,1-propanedicarboxylic    acid,-   [1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]eth-yl]cyclohexyl]acetic    acid,-   5,5-bis(hydroxymethyl)-7-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]heptanoic    acid,-   5,5-bis(hydroxymethyl)-7-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]heptanoic    acid,-   5-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethoxy]isophthalic    acid,-   2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzoic    acid,-   4-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]butyric    acid, etc.

Moreover, the compound represented by the general formula (XII) may beactivated with a carboxy group activating agent, and then, reacted withan amino acid ester or amino alcohol acetic acid ester, or alternativelyreacted with an amino acid ester or amino alcohol acetic acid ester inthe presence of a condensing agent to prepare the corresponding aminoacid ester derivative or amino alcohol acetic acid ester derivative.Further, this amino acid ester derivative or amino alcohol acetic acidester derivative may be hydrolyzed with an acid or base to prepare thecorresponding amino acid derivative or amino alcohol derivative. Thecompounds thus prepared are also included within the compounds of thisinvention represented by the general formula (I).

Specific examples of the carboxy group activating agent may includeoxalyl chloride, thionyl chloride, etc. Specific examples of thecondensing agent may include dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminoprpoyl)-carbodiimide hydrochloride,benzotriazol-1-yloxytris(dimeth-ylamino)phosphonium hexafluorophosphate,benzotriazol-1-yl-oxytrispyrrolidinophosphonium hexafluorophosphate,O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate, 2-bromo-1-ethylpyrydinium tetrafluoroborate,2-fluoro-1-ethylpyridinium tetrafluoroborate, etc. Specific examples ofthe amino acid ester may include ethyl aminoacetate, ethyl3-aminopropionate, ethyl 4-aminobutyrate, diethyl iminodiacetate,tris(acetoxy-methyl)aminomethane, etc. The bases to be used forhydrolysis may include lithium hydroxide, sodium hydroxide, potassiumhydroxide, potassium carbonate, etc. and the acids may includehydrochloric acid, trifluoroacetic acid, etc.

Specific examples of the amino acid ester derivative, amino alcoholacetic acid ester derivative, amino acid derivative and amino alcoholderivative thus prepared may include:

-   N-[1-[2-[1-[N-[tris(hydroxymethyl)methyl]carbamoylmethyl]cy-clohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxyamide,-   2-acetoxymethyl-2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetamido-1,3-diacetoxypropane,-   diethyl    2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarbox-amido]piperidin-1-yl]ethyl]cyclohexyl]acetyliminodiacetate,-   2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetyliminodiacetic    acid,-   ethyl    4-[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarbox-amido]piperidin-1-yl]ethyl]cyclohexyl]acetamido]butyrate,-   ethyl    [2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxa-mido]piperidin-1-yl]ethyl]cyclohexyl]acetamido]acetate,-   [2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetamido]acetic    acid,-   ethyl    3-[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarbox-amido]piperidin-1-yl]ethyl]cyclohexyl]acetamido]propionate,-   3-[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetamido]propionic    acid,-   ethyl    4-[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarbox-amido]piperidin-1-yl]ethyl]cyclopentyl]acetamido]butyrate,-   N-[1-[2-[1-[N,N-bis[N-tris(acetoxymethyl)methyl]carbamoylmethyl]carbamoylmethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxyamide,-   N-[1-[2-[1-[N,N-bis[N-tris(hydroxymethyl)carbamoylmethyl]-carbamoylmethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxyamide,-   [2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]acetamido]acetic    acid,-   4-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetamido]butyric    acid,-   2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]acetyliminodiacetic    acid,-   tetraethyl    2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]acetylimino-N,N-bis(acetyliminodiacetate),-   2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]acetylimino-N,N-bis(acetyliminodiacetic    acid), etc.

The carboxamide derivative may be prepared by reacting a compoundrepresented by the general formula (XII) with ammonia, an ammonium salt,an amine, an amine salt, a sulfonamide, etc., in the presence of acondensing agent. Specific examples of the amine may include morpholine,2-methoxycarbonylaniline, pyrazinylamine, etc. Specific examples of thesulfonamide may include methanesulfonamide and the like. Of thesederivatives, the ester derivative may be hydrolyzed with an acid or baseto prepare the corresponding carboxylic acid. These carboxamidederivatives are also included within the compounds of this inventionrepresented by the general formula (I).

Specific examples of the condensing agent may includedicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminoprpoyl)-carbodiimidehydrochloride, benzotriazol-1-yloxytris-(dimethylamino)phosphoniumhexafluorophosphate, benzotriazol-1-yloxytrispyrrolidinophosphoniumhexafluorophosphate,O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluoro-phosphate, 2-bromo-1-ethylpyrydimium tetrafluoroborate,2-fluoro-1-ethylpyridimium tetrafluoroborate, etc.

The reaction is carried out in an organic solvent such asdichloromethane, chloroform, tetrahydrofuran or N,N-dimethylformamide ata temperature of from room temperature to reflux temperature.

The bases to be used for hydrolysis may include lithium hydroxide,sodium hydroxide, potassium hydroxide, potassium carbonate, etc., andthe acids may include hydrochloric acid, trifluoroacetic acid, etc.

Specific examples of the carboxamide derivative may include:

-   N-[1-[2-[1-(carbamoylmethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   N-[1-[2-[1-(1-methanesulfonylcarbamoylmethyl)cyclohexyl]eth-yl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-(1,1-dimethylcarbamoylmethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancaroxamide,-   N-[1-[2-[1-(2-morpholin-4-yl-2-oxoethyl)cyclohexyl]ethyl]-piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetylamino]benzoic    acid,-   N-[1-[2-[1-[1-(pyrazin-2-yl)carbamoylmethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-(1,1-dimethylcarbamoylmethyl)cyclohexyl]ethyl]-piperidin-4-yl]-N-(5-methylpiperidin-2-yl)-2-furancarboxamide,-   N-[1-[2-[1-(2-morpholin-4-yl-2-oxoethyl)cyclohexyl]ethyl]-piperidin-4-yl]-N-(5-methylpiperidin-2-yl)-2-furancarboxamide,-   2-[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetylamino]benzoic    acid,-   N-[1-[2-[1-(carbamoylmethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,    etc.

The carboxamide derivative may be further converted to a nitrilederivative in the presence of a sulfonyl chloride (e.g., methanesulfonylchloride or benzenesulfonyl chloride) and triethylamine. The nitrilederivatives are also included within the compounds of this inventionrepresented by the general formula (I).

The reaction is carried out in an organic solvent such asdichloromethane, chloroform, tetrahydrofuran or N,N-dimethylformamide ata temperature of from room temperature to reflux temperature.

Specific examples of the nitrile derivative may includeN-[1-[2-[1-(cyanomethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,N-[1-[2-[1-(cyanomethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,etc.

The nitrile derivative may further be converted to a tetrazolederivative by reacting it with trimethylsilyl azide. The tetrazolederivatives are also encompassed by the compounds of this inventionrepresented by the general formula (I).

The reaction is carried out in an organic solvent such as benzene,toluene, xylene, tetrahydrofuran or 1,4-dioxane at a temperature of fromice cooling temperature to reflux temperature.

The tetrazole derivative may be converted to another tetrazolederivative by reacting it with trimethylsilyl diazomethane. The lattertetrazole derivatives are also included within the compounds of thisinvention represented by the general formula (I).

The reaction is carried out in an organic solvent such as benzene,toluene, xylene, tetrahydrofuran or 1,4-dioxane at a temperature of fromice cooling temperature to reflux temperature.

Specific examples of the tetrazole derivative may include:N-[1-[2-[1′-(2-tetrazolylethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,N-[1-[2-[1-(2-tetrazolylethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,N-[1-[2-[1-[2-(2-methyl-2H-tetrazol-5-yl)ethyl]cyclohexyl]-ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarbo-xamide,N-[1-[2-[1-[2-(1-methyl-1H-tetrazol-5-yl)ethyl]cyclohexyl]-ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,etc.

The nitrile drivative may, for example, be further converted to ahydroxycarbamidoyl derivative by reacting it with hydroxylamine in thepresence of a base such as sodium hydrogencarbonate or potassiumcarbonate. The hydroxycarbamidoyl derivatives are also included withinthe compounds of this invention represented by the general formula (I).

The reaction is carried out in an organic solvent such as benzene,toluene, xylene, tetrahydrofuran or 1,4-dioxane at a temperature of fromice cooling temperature to reflux temperature.

Specific examples of the hydroxycarbamoyl derivative may includeN-[1-[2-[1-[2-(N²-hydroxycarbamidoyl)ethyl]-cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancar-boxamideand the like.

The hydroxycarbamidoyl derivative may, for example, be converted to athioxooxadiazole derivative by reacting it with1,1-thiocarbonyldiimidazole. The thioxooxadiazole derivatives are alsoincluded within the compounds of this invention represented by thegeneral formula (I).

The reaction is carried out in an organic solvent such as acetonitrile,benzene, toluene, xylene, tetrahydrofuran or 1,4-dioxane at atemperature of from ice cooling temperature to reflux temperature.

Specific examples of the thioxooxadiazole derivative may includeN-[1-[2-[1-[2-(2H-5-thioxo-1,2,4-oxadiazol-3-yl)ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamideand the like.

The hydroxycarbamidoyl derivatives may, for example, be converted to ahydroxymethoxycarbonylcarbamidoyl derivative by reacting it with methylchloroformate in the presence of a base such as pyridine. Thehydroxymethoxycarbonylcarbamidoyl derivatives are also included withinthe compounds of this invention represented by the general formula (I).

The reaction is carried out in an organic solvent such asN,N-dimethylformamide, acetonitrile, benzene, toluene, xylene,tetrahydrofuran or 1,4-dioxane at a temperature of from ice coolingtemperature to reflux temperature.

Specific examples of the hydroxymethoxycarbamidoyl derivative mayinclude methyl1-[1-hydroxyimino-3-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]propyl]carbamateand the like.

The hydroxymethoxycarbonylcarbamidoyl derivative may, foe example, beconverted to an oxooxadiazole derivative by reacting it with a base suchas 1,8-diazabicyclo[5.4.0]-7-undecene. The oxooxadiazole derivatives arealso included within the compounds of this invention represented by thegeneral formula (I).

The reaction is carried out in an organic solvent such as acetonitrile,benzene, toluene, xylene, tetrahydrofuran, or 1,4-dioxane at atemperature of from ice cooling temperature to reflux temperature.

Specific examples of the oxooxadiazole derivative may includeN-[1-[2-[1-[2-(2H-oxo-1,2,4-oxadiazol-3-yl)eth-yl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamideand the like.

The hydroxamic acid derivative may be prepared by reacting a compoundrepresented by the general formula (XII) with hydroxylaminehydrochloride, O-(tert-butyl)hydroxylamine hydrochloride or the like.The butyl group may be deprotected by acid (e.g., hydrochloric acid ortrifluoroacetic acid). The hydroxamic acid derivatives are also includedwithin the compounds of this invention represented by the generalformula (I).

Specific examples of the hydroxamic acid derivative may include:

-   tert-butyl    [1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarbo-xamido]piperidin-1-yl]ethyl]cyclohexyl]-acetohydroxamate,-   [1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetohydroxamic    acid,-   tert-butyl    [1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperi-din-1-yl]ethyl]cyclohexyl]acetohydroxamate,-   [1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetohydroxamic    acid, etc.

A compound represented by the general formula (XIII):

wherein

X is CH or N; and

Yc is a group of the general formula (II):

or a group of the general formula (II-a):

wherein a and b are each an integer of 0-6;T is O or N—R¹⁵ wherein R¹⁵ is H, a C1-C6 alkyl group, a benzyl group ora phenethyl group;R¹ is a group of the general formula (IV):

wherein d is an integer of 0-6; R³ is —(CH₂)_(e)OH wherein e is aninteger of 0-6; R⁴ and R⁵ may be the same or different and are eachindependently H or —(CH₂)_(e)R⁶ wherein R⁶ is a carboxy group, a hydroxygroup or a dihydroxy C1-C6 alkylphenoxy group, which is included withinthe compounds of this invention represented by the general formula (I),may be prepared by hydrolysis of the corresponding acetic acid esterform, benzoyl ester form or 2-furoyl ester form with a base (e.g.,lithium hydroxide, sodium hydroxide, potassium hydroxide or potassiumcarbonate), or alternatively by hydrolysis of the corresponding acetalform (e.g., the 2-phenyl-1,3-dioxane-5-yl form,2,2-dimethyl-1,3-dioxan-5-yl form or methoxymethyl form) with an acid(e.g., hydrochloric acid or p-toluenesulfonic acid), or hydrolysis ofthe corresponding silyl ether derivative with an acid (e.g.,hydrochloric acid or p-toluenesulfonic acid) or by treatment thederivative with a fluorinating agent (e.g., tetra-n-butylammoniumfluoride).

The hydrolysis reaction is carried out in water or an organic solventsuch as methanol, ethanol or 2-propanol at a temperature of from icecooling temperature to reflux temperature. The treatment with thefluorinating agent is carried out in an organic solvent such asdichloromethane, chloroform, diethyl ether or tetrahydrofuran at atemperature of from ice cooling temperature to reflux temperature.

Specific examples of the compound represented by the general formula(XIII) may include:

-   N-[1-(1-(3-hydroxypropyl)cyclohexylmethyl)piperidin-4-yl]-N-(5-methylpiperidin-2-yl)-2-furancarboxamide,-   N-[1-[2-[1-(4-hydroxy-3-hydroxymethylbutyl)cyclohexyl]ethyl-]piperidin-4-yl]-N-(5-methylpiperidin-2-yl)-2-furancarboxamide,-   N-[1-[2-[1-[5-hydroxy-3,3-bis(hydroxymethyl)pentyl]cyclohex-yl]ethyl]piperidin-4-yl]-N-(5-methylpiperidin-2-yl)-2-furan-carboxamide,-   N-[1-[2-[1-[1,3-dihydroxypropan-2-yl]cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpiperidin-2-yl)-2-furancarboxamide,-   N-[1-[2-[1-[1,3-dihydroxypropan-2-yl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-(4-hydroxy-3-hydroxymethylbutyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   5,5-bis(hydroxymethyl)-7-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]heptanoic    acid,-   5,5-bis(hydroxymethyl)-7-[1-[2-[4-[N-(p-tolyl)-2-furancarbo-xamido]piperidin-1-yl]ethyl]cyclohexyl]heptanoic    acid,-   N-[1-[2-(1-(2-hydroxyethyl)cyclohexyl)ethyl]piperidin-4-yl]-N-(5-methylpiperidin-2-yl)-2-furancarboxamide,-   N-[1-[2-[1-[5-hydroxy-3,3-bis(hydroxymethyl)pentyl]cyclohex-yl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-[2-[3,5-bis(hydroxymethyl)phenoxy]ethyl]cyclohex-yl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-[2-[3,5-bis(hydroxymethyl)phenoxy]ethyl]cyclohex-yl]ethyl]piperidin-4-yl]-N-(5-methylpiperidin-2-yl)-2-furan-carboxamide,-   N-[1-[2-[1-(2-hydroxyethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-(2-hydroxyethyl)cyclobutyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-(2-hydroxyethyl)cyclooctyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[4-(2-hydroxyethyl)tetrahydropyran-4-yl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-benzyl-4-(2-hydroxyethyl)piperidin-4-yl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,    etc.

An amine derivative represented by the general formula (XIV):

wherein

X is CH or N; and

Yd is a group of the general formula (XV):

or a group of the general formula (XV-a):

or a group of the general formula (XVI):

wherein a, b, c and d are each an integer of 0-6,which is included within the compounds of this invention represented bythe general formula (I), may be prepared by deprotection of thecorresponding tert-butoxycarbonyl form in the presence of an acid (e.g.,hydrochloric acid or trifluoroacetic acid).

The reaction is carried out in water or an organic solvent such asmethanol, ethanol, dichloromethane, 1,4-dioxane or ethyl acetate at atemperature of from ice cooling temperature to reflux temperature.

Specific examples of the compound represented by the general formula(XIV) may include:

-   N-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpiperidin-2-yl)-2-furancarboxamide,-   N-[1-[3-(2-aminophenyl)propyl]piperidin-4-yl]-N-(5-methylpi-peridin-2-yl)-2-furancarboxamide,-   N-[1-[3-(2-aminophenyl)propyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-(2-guanidinoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpiperidin-2-yl)-2-furancarboxamide,    etc.

The amine derivative represented by the general formula (XIV) wherein Ydhas a general formula (XVI) may be converted to an alkyl derivative oracyl derivative by a conventional method. The amine derivativerepresented by the general formula (XIV) wherein Yd has a generalformula (XV) may be converted to a sulfonyl derivative by a conventionalmethod.

Specific examples of the compound thus prepared may include:

-   N-[2-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]phenyl]-N-(cyclohexylacetyl)aminoacetic    acid,-   tert-butyl    N-[2-[2-[4-[N-(p-tolyl)-2-furancarboxami-do]piperidin-1-yl]ethyl]phenyl]-N-(cyclohexylacetyl)aminoacetate,-   N-[2-[3-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-propyl]phenyl]-N-(cyclohexylpropionyl)aminoacetic    acid,-   tert-butyl    N-[2-[3-[4-[N-(p-tolyl)-2-furancarboxami-do]piperidin-1-yl]propyl]phenyl]-N-(3-cyclohexylpropionyl)aminoacetate,-   N-[2-[3-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-propyl]phenyl]-N-(3-cyclohexylpropionyl)aminobutyric    acid,-   ethyl    3-[2-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxa-mido]piperidin-1-yl]ethyl]phenyl]-5-cyclohexylhydantoate,-   3-[2-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]pi-peridin-1-yl]ethyl]phenyl]-5-cyclohexylhydantoic    acid,-   ethyl    N-[2-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxa-mido]piperidin-1-yl]ethyl]phenyl]aminoacetate,-   ethyl    N-[(1-methoxycarbonylmethylcyclohexyl)acetyl]-N-[2-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]phenyl]aminoacetate,-   N-[(1-carboxymethylcyclohexyl)acetyl]-N-[2-[2-[4-[N-(5-meth-ylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]phe-nyl]aminoacetic    acid,-   N-[1-[3-[2-(3-cyclohexylpropionamido)phenyl]propyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   N-[1-[2-[2-(3-cyclohexylureido)phenyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   N-[1-[3-[2-(4-cyclohexylbutyramido)phenyl]propyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,-   methyl    1-[N-[2-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancar-boxamido]piperidin-2-yl]ethyl]phenyl]carbamoylmethyl]cyclohexylacetate,-   1-[N-[2-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]phenyl]carbamoylmethyl]cyclohexylacetic    acid,-   N-[1-[3-[2-(3-cyclohexylureido)phenyl]propyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[3-[2-(3-cyclohexylthioureido)phenyl]propyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-(2-methanesulfonylaminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-(p-toluenesulfonylamino)ethyl]cyclohexyl]ethyl]-piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-[2-(4-chlorobenzenesulfonylamino)ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide,-   N-[1-[2-[1-[2-(1,2-di-tert-butoxycarbonylguanidino)ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,    etc.

A compound represented by the general formula (V):

wherein

X is CH or N; and

Y_(a) is a group of the general formula (VI):

or a group of the general formula (VI-a):

wherein T is O or N—R¹⁵ wherein R¹⁵ is H, a C1-C6 alkyl group, a benzylgroup or a phenethyl group,or a group of the general formula (VII):

or a group of the general formula (VIII):

whereina, b and c are each an integer of 0-6;

Z is CH₂ or NH; W is O or S;

R⁹ is H, a C1-C6 alkoxycarbonyl group, a benzyloxy carbonyl group, acarboxy group, a 2-phenyl-1,3-dioxan-5-yl group, or a2,2-dimethyl-1,3-dioxan-5-yl group;R¹⁰ is H or a group of the general formula (IX):

wherein d is an integer of 0-6; andR¹¹, R¹², and R¹³ may be the same or different and are eachindependently H or —(CH₂)_(e)R¹⁴ wherein e is 0-6, R¹⁴ is a C1-C6alkanoyloxy group, a benzoyloxy group, a 2-furoyloxy group, a C1-C6alkoxy C1-C6 alkoxy group, a C1-C6 alkoxycarbonylphenoxy group, a diC1-C6 alkoxycarbonylphenoxy group, a di C1-C6 alkanoyloxy C1-C6alkylphenoxy group, a C1-C6 alkyldiarylsiloxy group, a carboxy group, aC1-C6 alkoxycarbonyl group, a benzyloxycarbonyl group, a cyano group, ora C1-C6 alkylsulfonamido group,which is an intermediate compound for the synthesis of the compounds ofthis invention represented by the general formula (I), may be preparedby reacting a compound represented by the general formula (XVII):

wherein X is CH or N,with a compound represented by the general formula (XVIII):

or with a compound of the general formula (XIX):

wherein P is a derivatized form with an activated hydroxy group asrepresented by a halogen atom, a methanesulfonyloxy group, or atrifluoromethanesulfonyloxy group;a, b and c are each an integer of 0-6;

Z is CH₂ or NH; W is O or S;

R⁹ is H, a C1-C6 alkoxycarbonyl group, a benzyloxycarbonyl group, acarboxy group, a 2-phenyl-1,3-dioxan-5-yl group, or a2,2-dimethyl-1,3-dioxan-5-yl group,or a group of the general formula (IX):

whereind is an integer of 0-6; andR¹¹, R¹², and R¹³ may be the same or different and are eachindependently H or —(CH₂)_(e)R¹⁴ wherein e is 0-6; and R¹⁴ is a C1-C6alkanoyloxy group, a benzoyloxy group, a 2-furoyloxy group, a C1-C6alkoxy C1-C6 alkoxy group, a C1-C6 alkoxycarbonylphenoxy group, a diC1-C6 alkoxycarbonylphenoxy group, a di C1-C6 alkanoyloxy C1-C6alkylphenoxy group, a C1-C6 alkyldiarylsiloxy group, a carboxy group, aC1-C6 alkoxycarbonyl group, a benzyloxycarbonyl group, a cyano group, ora C1-C6 alkylsulfonamido group,in the presence of a base, or alternatively by reductive amination inthe presence of a reducing agent using an aldehyde compound representedby the general formula (XX), (XX-a) or (XXI), or a ketone compoundrepresented by the general formula (XXII), or a hemiacetal compoundrepresented by the general formula (XXIII) or (XXIII-a).

wherein T is N—R¹⁵ wherein R¹⁵ is H, a C1-C6 alkyl group, a benzyl groupor a phenethyl group,

The reaction is carried out in water or an organic solvent such as1,2-dichloroethane, dichloromethane, tetrahydrofuran, acetonitrile,1,4-dioxane or methanol at a temperature of from ice cooling temperatureto reflux temperature.

Specific examples of the compound of the general formula (V) mayinclude:

-   2-[1-(cyclohexylmethyl)piperidin-4-ylamino]-5-methylpyridine,-   2-[1-(2-cyclohexylethyl)piperidin-4-ylamino]-5-methylpyridine,-   2-[1-(3-cyclohexylpropyl)piperidin-4-ylamino]-5-methylpyridine,-   2-[1-(4-cyclohexylbutyl)piperidin-4-ylamino]-5-methylpyridine,-   2-[1-(2-cyclooctylethyl)piperidin-4-ylamino]-5-methylpyridine,-   1-(3-cyclohexylpropyl)-4-(p-toluidino)piperidine,-   2-(1-cyclohexylpiperidin-4-ylamino)-5-methylpyridine,-   2-[1-[3-[2-(cyclohexylacetamido)phenyl]propyl]piperidin-4-ylamino]-5-methylpyridine,-   2-[1-[2-[2-(cyclohexylacetamido)phenyl]ethyl]piperidin-4-yl-amino]-5-methylpyridine,-   methyl    [1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethy]cyclohexyl]acetate,-   methyl    [1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethy]cyclopentyl]acetate,-   methyl    1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]-ethyl]cyclohexanecarboxylate,-   1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethyl]cyclohexanecarboxylic    acid,-   methyl    4-[1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethyl]cyclohexyl]butyrate,-   triethyl    3-[1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethy]cyclohexyl]-1,1,1-propanetricarboxylate,-   dimethyl    3-[1-[2-[4-(p-toluidino)piperidin-1-yl]eth-yl]cyclohexyl]-1,1-propanedicarboxylate,-   methyl    [1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohe-xyl]acetate,-   3-[1-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]methylcyclohexyl]propyl    acetate-   2-[2-[1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]eth-yl]cyclohexyl]ethyl]-1,3-diacetoxypropane,-   2-[1-[2-[1-(4-methoxymethoxy)-3-(methoxymethyl)butyl]cyclohexyl]ethyl]piperidin-4-ylamino]-5-methylpyridine,-   2-(acetoxymethyl)-2-[2-[1-[2-[4-(5-methylpyridin-2-ylamino)-piperidine-1-yl]ethyl]cyclohexyl]ethyl]-1,4-diacetoxypropane,    2-[1-[2-[1-(2-phenyl-1,3-dioxan-5-yl)cyclohexyl]ethyl]piperidin-4-ylamino]-5-methylpyridine,-   1-[2-[1-(2,2-dimethyl-1,3-dioxan-5-yl)cyclohexyl]ethyl-4-(p-toluidino)piperidine,-   methyl    5,5-bis(benzoyloxymethyl)-7-[1-[2-[4-(5-methylpyri-din-2-ylamino)piperidin-1-yl]ethyl]cyclohexyl]heptanoate,-   methyl    5,5-bis(benzoyloxymethyl)-7-[1-[2-[4-(p-toluidino)-piperidin-1-yl]ethyl]cyclohexyl]heptanoate,-   2-[2-[1-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]eth-yl]-1,3-diacetoxypropane,-   2-[1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethyl]-cyclohexyl]ethyl    2-furancarboxylate-   2-[1-[2-[1-(2-cyanoethyl)cyclohexyl]ethyl]piperidin-4-ylami-no]-5-methylpyridine,-   tert-butyl    2-[1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethyl]cyclohexyl]ethyl]carbamate,-   N-[2-[1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethyl]cyclohexyl]ethyl]methanesulfonamide,-   N-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-ylmethyl]phe-nyl]cyclohexylacetamide,-   N-[2-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]phenyl]cyclohe-xylacetamide,-   N-[2-[3-[4-(p-toluidino)piperidin-1-yl]propyl]phenyl]cyclohexylacetamide,-   tert-butyl    [2-[3-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]propyl]phenyl]carbamate,-   tert-butyl    [2-[3-[4-(p-toluidino)piperidin-1-yl]propyl]phe-nyl]carbamate,-   1-[2-[1-(2-cyanoethyl)cyclohexyl]ethyl]-4-(p-toluidino)pipe-ridine,-   dimethyl    5-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]-cyclohexyl]ethoxy]isophthalate,-   1,3-diacetoxymethyl-5-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzene,-   1,3-diacetoxymethyl-5-[2-[1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzene,-   2-[1-[2-[4-(p-toluidino)piperi din-1-yl]ethyl]cyclohexyl]eth-anol,-   methyl    4-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclo-hexyl]butyrate,-   triethyl    3-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]-cyclohexyl]-1,1,1-propanetricarboxylate,-   2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclobutyl]eth-anol,-   2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclooctyl]eth-anol,-   2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]tetrahydropyran-4-yl]ethanol,-   1-[2-[1-benzyl-4-[2-(tert-butyldiphenylsiloxy)ethyl]piperidin-4-yl]ethyl]-4-toluidinopiperidine,    etc.

Specific examples of the compound of the general formula (XVII) mayinclude 2-(piperidin-4-ylamino)-5-methylpyridine,4-(p-toluidino)piperidine, etc.

Specific examples of the compound of the general formula (XVIII) mayinclude (bromomethyl)cyclohexane, (2-bromoethyl)-cyclohexane,(3-bromopropyl)cyclohexane, (4-bromobutyl)cyclo-hexane, methyl1-(2-bromoethyl)cyclohexylacetate, methyl1-(2-bromoethyl)cyclopentylacetate,3-[1-(trifluoro-methanesulfonyloxymethyl)cyclohexyl]propyl acetate,3-[1-(2-bromoethyl)clohexyl]propionitrile, etc.

Specific examples of the compound of the general formula (XIX) mayinclude N-[2-(2-bromoethyl)phenyl]cyclohexylacetam-ide, 2-nitrobenzylbromide, (2-bromoethyl)-2-nitrobenzene, (3-bromopropyl)-2-nitrobenzene,tert-butyl [2-(3-bromopropyl)phenyl]carbamate, etc.

Specific examples of the compound of the general formula (XX) mayinclude cyclooctylacetaldehyde, methyl1-(formylmeth-yl)cyclohexanecarboxylate, benzyl1-(formylmethyl)cyclohex-anecarboxylate, methyl4-[1-(formylmethyl)cyclohexyl]butyrate, triethyl3-[1-(formylmethyl)cyclohexyl]-1,1,1-propanetricar-boxylate, dimethyl3-[1-(formylmethyl)cyclohexyl]-1,1-propanedicarboxylate,2-[2-[1-(formylmethyl)cyclohexyl]eth-yl]-1,3-diacetoxypropane,[1-(4-methoxymethoxy)-3-(methoxymethoxymethyl)butyl]cyclohexylacetaldehyde,1-(2-phenyl-1,3-dioxan-5-yl)cyclohexylacetaldehyde,1-(2,2-dimethyl-1,3-dioxan-5-yl)cyclohexylacetaldehyde,

2-(acetoxymethyl)-2-[2-[1-(formylmethyl)cyclohexyl]ethyl]-1,4-diacetoxybutane,methyl 5,5-bis(benzoyloxymethyl)-7-[1-(formylmethyl)cyclohexyl]

ethyl]heptanoate,N-[2-[1-(formylmethyl)cyclohex-yl]ethyl]methanesulfonamide,1-(2-phthalimidoethyl)cyclo-hexylacetaldehyde, etc.

Specific examples of the compound of the general formula (XX-a) mayinclude[1-benzyl-4-[2-(tert-butyldiphenylsilox-y)ethyl]piperidin-4-yl]acetaldehydeand the like.

Specific examples of the compound of the general formula (XXI) mayinclude N-[2-(2-formylethyl)phenyl]cyclohexyl-acetamide and the like.

Specific examples of the compound of the general formula (XXII) mayinclude cyclohexanone and the like.

Specific examples of the compound of the general formula (XXIII) mayinclude 3-oxaspiro[5.5]undecan-2-ol, 3-oxaspiro-[5.3]nonan-2-ol,3-oxaspiro[5.7]tridecan-2-ol, etc.

Specific examples of the base may include organic bases such astriethylamine, pyridine, diisopropylamine, diisopropylethylamine, and1,8-diazabicyclo[5.4.0]-7-undecene, or inorganic bases such as sodiumhydroxide, potassium hydroxide, potassium carbonate, and sodiumhydrogencarbonate. Specific examples of the reducing agent may includesodium borohydride, sodium triacetoxyborohydride, sodiumcyanoborohydride, etc.

The compound of the general formula (V) may also be synthesized via aphthalimide derivative (XXIV) or a nitro derivative (XXV) as shown inReaction Scheme 1.

The compound of the general formula (XVIII):

may be synthesized according to the process as shown in Reaction Scheme2.

By virtue of inhibition of the μ opioid receptors, the compounds of thisinvention as mentined above are useful as a therapeutic or prophylacticagent for side effects which are caused by the μ receptor agonists suchas constipation, nausea/emesis, and itch, as well as for diseases suchas idiopathic constipation, postoperative ileus, paralytic ileus,irritable bowel syndrome and chronic pruritus.

Some of the compounds of this invention represented by the generalformula (I) are prodrugs, and thus, they may be metabolized in vivo andconverted to novel opioid μ receptor antagonists. Main sites subjectedto metabolism will be illustrated in the general formulae (I) to (IV):

-   -   1) Hydroxylation of a methyl group    -   2) Hydroxylation of an aromatic ring    -   3) N-Oxidation of a nitrogen atom    -   4) Hydroxylation of a piperidine ring    -   5) Hydroxylation of a methylene chain    -   6) Hydroxylation of a cycloalkyl group    -   7) Hydrolysis of an ester group and hydroxylation of an alkyl        chain    -   8) Glucuronate, sulfate or glutathione conjugates of the above        compounds

The compounds of this invention represented by the general formula (I)may be converted to pharmacologically

acceptable acid or base addition salts, if desired, and these acid orbase addition salts also fall under the scope of this invention. Theacid addition salts may include salts with an inorganic acid such ashydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acidand salts with an organic acid such as acetic acid, succinic acid,oxalic acid, malic acid, tartaric acid, fumaric acid, maleic acid,citric acid, malonic acid, lactic acid, methanesulfonic acid,p-toluenesulfonic acid, mandelic acid, suberic acid, phthalic acid, orterephthalic acid. The base addition salts may include salts with aninorganic base such as sodium salt, potassium salt or various ammoniumsalts and salts with an organic base.

The compounds represented by the general formula (I) when used as amedicament may be formulated into various dosage forms of preparations.More specifically, the preparations may be orally administered in theform of tablets, sugar coated tablets, hard capsules, soft capsules,enteric preparations, liquid preparations such as solutions, emulsionsor suspensions. The preparations may be parenterally administered in theform of liquid preparations such as injections, suppositories,infusions, solutions, emulsions or suspensions.

In preparing these preparations, conventional additives such asexcipients, stabilizers, antiseptics, solubilizing agents, humectants,emulsifying agents, lubricants, sweeteners, coloring agents, flavors,tonicity agents, and antioxidants may be added for formulating thepreparations.

Administration routes and doses of the opioid A receptors according tothis invention may be adequately selected depending on variouspreparation forms, the gender of patients or the severity of diseases,but a daily dose of the active ingredient will be 1 to 100 mg.

BEST MODE FOR CARRYING OUT THE INVENTION

Formulation Examples will be illustrated below.

FORMULATION EXAMPLE 1

Gelatin hard capsule Compound described in Example 4D-8  20 mg Cornstarch 200 mg Magnesium stearate  10 mg Total 230 mg

All the ingredients were uniformly blended and filled into a gelatinhard capsule to prepare a gelatin hard capsule with a content of 460 mg.

FORMULATION EXAMPLE 2

Gelatin hard capsule Compound described in Example 4D-6 20 mg Cornstarch 89 mg Crystalline cellulose 89 mg Magnesium stearate  2 mg Total200 mg 

All the ingredients were uniformly blended and filled into a gelatinhard capsule to prepare a gelatin hard capsule with a content of 200 mg.

FORMULATION EXAMPLE 3

Gelatin soft capsule (Liquid medicine) Compound described in Example3D-3 20 mg Middle chain fatty acid triglyceride 160 mg Polyoxyethylenehydrogenateed castor oil 20 mg Subtotal 200 mg (Coating film) Gelatin100 mg Glycerol 30 mg Methyl parabenzoate 0.2 mg Propyl paraoxybenzoate0.05 mg Purified water q.s. Subtotal 140 mg Total 340 mg

The coating film was prepared from a coating film solution previouslydissolved by being heated in a rotary apparatus for preparing softcapsules, and the liquid medicament previously dissolved uniformly wasencapsulated with the coating film and then molded. Thereafter, thecapsules were thoroughly dried.

FORMULATION EXAMPLE 4

Tablet Compound described in Example 3B-1 10 mg Corn starch 45 mgCrystalline cellulose 35 mg Polyvinyl pyrrolidone 4 mg (in the form of a10% aqueous solution) Carboxymethylcellulose sodium 4.5 mg Magnesiumstearate 0.5 mg Talc 1 mg Total 100 mg

The active ingredient, starch and cellulose were sieved and blendedcompletely. An aqueous polyvinyl pyrrolidone solution was admixed withthe powder thus obtained and passed through a No. 14 mesh sieve. Thegranular product thus prepared was dried at 50-60° C. and passed througha No. 18 mesh sieve. Subsequently, carboxymethylcellulose sodium,magnesium stearate and talc, which had been previously passed through aNo. 60 mesh sieve, were added to the granular product and blended andthen compressed to tablets, each weighing 100 mg, by means of a tabletmachine.

FORMULATION EXAMPLE 5

Tablet Compound described in Example 2-33 250 mg Crystalline cellulose400 mg Thyroid  10 mg Magnesium stearate  5 mg Total 665 mg

All the ingredients were uniformly blended and then compressed totablets, each weighing 665 mg, by means of a tablet machine.

A suspension containing an active ingredient at 5 mg per 5 mL of a dosewas prepared as described below.

Suspension Compound described in Example 2-34 5 mgCarboxymethylcellulose sodium 50 mg Simple syrup 1.25 mL Aqueoussolution of benzoic acid 0.10 mL Flavors q.s. Purified water q.v. tomake up to a total volume of 5 mL Total 5 mL

The active ingredient was passed through a No. 45 mesh sieve and blendedwith carboxymethylcellulose sodium and simple syrup to prepare a paste.The aqueous solution of benzoic acid and flavors were diluted with asmall amount of purified water and added to the paste obtained abovewith stirring. Subsequently, purified water was further added to make upto the desired volume.

The μ antagonistic activity of the compounds of this invention (PA₂value) was determined according to the electric stimulation method for aspecimen of the ileum longitudinal muscle of guinea pig.

The longitudinal muscle specimen was prepared by sacrificing a guineapig (Hartley strain, male) with bleeding and then removing the ileum.The specimen was hung with a loading of 0.5 g in a Magnus equipmentfilled with 20 ml of a nutrient solution (Krebs-Henselite solution, 37°C., aerating with 95% O₂-5% CO₂) and isometric contraction was recorded.The specimen was equilibrated in the nutrient solution over one hour,and then, electric stimulation was given at a voltage capable ofproviding the maximum contraction (0.1 Hz, 1 msec duration). Aftercontraction was stabilized, morphine (a μ receptor agonist), wascumulatively added and, after washing, dosing was discontinued for onehour. Electric stimulation was again initiated and, after contractionwas stabilized, the compound of this invention was added and, 15 minutesafter the addition, morphine was cumulatively added. Contraction heights(mm) before and after morphine addition were measured from the chartrecording contraction by electric stimulation, and then, contractioninhibition rate (%) was calculated according to the following equation1:

Contraction inhibition (%)=[(a−b)/a]×100

a: contraction height before morphine addition (mm)

b: contraction height after morphine addition (mm)

Morphine concentration-response curves were prepared in the absence andpresence of the compound of this invention by setting logarithmicconcentrations of morphine on the axis of abscissas and plottingcontraction rates (%) on the axis of ordinates. At the point of 50%contraction inhibition in the morphine concentration-response curve, thedistance (mm) of the morphine concentration-response curve between thepresence of the compound of this invention and the absence thereof wasmeasured. Value of Log(CR-1) in the equation 2 was determined based onthe distance from a van Rossum's simplified table and pA2 value wascalculated.

Log(CR−1)=Log[B]+pA ₂  Equation 2

[B]: Concentration of the compound of this invention

Antagonistic activity of the compounds of this invention against the μreceptors (PA₂ value) is shown in Table 1.

TABLE 1 Antagonistic activity against μ receptor Example No. pA₂Compound 10 as disclosed in —* Japan Kokai 264460/1988 (Compound XI asshown before) Example 2-3 8.14 Example 2-6 8.15 Example 2-15 8.30Example 2-17 8.38 Example 2-18 8.86 Example 2-26 8.01 Example 2-31 8.58Example 2-33 8.67 Example 2-34 8.61 Example 3B-1 8.26 Example 3C-4 8.15Example 3D-3 8.05 Example 3G-2 8.12 Example 4A-1 8.13 Example 4A-4 8.36Example 4D-1 8.12 Example 4D-2 8.26 Example 4D-6 7.85 Example 4D-8 8.61Example 5B-1 8.66 Example 5B-4 8.42 Example 5B-6 8.23 *μ receptoragonistic activity was noted. EC₅₀ = 2.2 × 10⁻⁷ M

Antagonistic activity of the compounds of this invention against thecentral μ receptor was determined according to the analgesic assay bypressure stimulation to mice.

This assay method is a method for measuring pain threshold with an indexof pseudo-pain reaction of a mouse by pressing the mouse (ddY strain, 5weeks old, male) at his tail head using Randall-Selitto pressing device.Pseudo-pain reaction is meant to include looking back, biting, writhing,squealing, etc.

First, the threshold pressure was measured prior to administration ofthe compound of this invention. Then, the compound of this invention wassubcutaneously administered and 15 minutes after administration,morphine hydrochloride was subcutaneously administered at 10 mg/kg.Forty five minutes after morphine administration, the threshold pressurewas measured. In order to protect the tissues from damages, a maximumpressure of 750 g (cutoff pressure) was set and the threshold pressuresof the group given the compound of this invention and the control groupgiven the solvent were measured. Analgesic effect by morphine in eachgroup (%) was calculated according to Equation 3.

Analgesic effect (%)=[(Pt−Po)/(cut-off pressure 750 g−Po)]×100  Equation3

-   -   Po: pain threshold prior to administration of the compound of        this invention or a solvent (g)    -   Pt: pain threshold after morphine administration (g)    -   From the average value of analgesic effect in each administered        group (5-9 cases in each group), inhibition rate (%) of the        compound of this invention on morphine analgesic effect was        calculated according to Equation 4.

Inhibition rate (%)=[(Ao−At)/Ao]×100  Equation 4

-   -   Ao: average value (%) of analgesic effect of the control group        given a solvent    -   At: average value (%) of analgesic effect of the group given the        compound of this invention

A dose-response curve was prepared by setting logarithmic doses of thecompound of this invention on the axis of abscissas and plottinginhibition rates (%) on the axis of ordinates. The dose of the compoundof this invention to inhibit analgesic effect of morphine by 50% (AD₅₀value) was calculated from the curve.

Antagonistic activity of the compounds of this invention on theperipheral u receptor was determined by transporting ability of carbonpowder.

Mice (ddY strain, 5 weeks old, male) after fasted overnight weresubcutaneously administered with the compound of this invention. Thirtyminutes after administration, morphine hydrochloride was subcutaneouslyadministered at 10 mg/kg. Thirty minutes after morphine administration,5% carbon powder was orally administered. Thirty minutes afteradministration of the carbon powder, mice were sacrificed, andimmediately the stomach through the blind intestine was excised. Thedistance between the pyloric ring of the excised intestine and the tipof carbon powder and the full length of the small intestine (from thepyloric ring up to the ilocecal ring) were measured. Carbon powdermoving rates for the group given the compound of this invention and thecontrol group given the carbon powder were calculated according to

Moving rate (%)=(Mt/Mo)×100  Equation 5

-   -   Mo: full length of the small intestine (cm)    -   Mt: distance between the puloric ring and the tip of the carbon        atom

From the average value of moving rates in each administered group (3-6cases in each group), improving rate (%) of the compound of thisinvention on the lowering effect of carbon powder transporting abilityby morphine was calculated according to Equation 6.

Improving rate (%)=[(Et−Em)/(En−Em)]×100  Equation 6

-   -   En: average value of moving rates (%) for the group given a        solvent and the group not given morphine    -   Em: average value of moving rates (%) for the group given a        solvent and the control group given morphine    -   Et: average value of moving rates (%) of the group given the        compound of this invention and the group given morphine

A dose-response curve was prepared by setting logarithmic doses of thecompound of this invention on the axis of abscissas and plottingimproving rates (%) on the axis of ordinates. The dose of the compoundof this invention to improve the lowering effect of morphine ontransporting ability of carbon powder by 50% (ED₅₀ value) was calculatedfrom the curve.

The level of peripheral selectivity of the compounds of this inventioncan be evaluated from the rate of AD₅₀ value for antagonistic activityagainst the central μ receptor to ED₅₀ value for antagonistic activityagainst the peripheral u receptor (AD₅₀/ED₅₀). The higher the rate is,the higher the peripheral selectivity will become.

The peripheral selectivity (AD₅₀/ED₅₀) of the compounds of thisinvention is illustrated in Table 2.

TABLE 2 Peripheral selectivity Example No. AD₅₀(mg/kg) ED₅₀(mg/kg)AD₅₀/ED₅₀ Example 2-3 2.7 19.3 0.1 Example 3B-1 4.0 3.3 1.2 Example 3D-316.7 8.4 2.0 Example 3G-2 5.3 5.3 1.0 Example 4D-6 7.7 3.0 2.6 Example4D-8 16.3 5.5 3.0

This invention will be more fully explained by way of the followingexamples. However, these examples are provided only for the purpose ofillustrating this invention, and are not to be limiting this invention.

PREPARATION EXAMPLE 1A-1 Ethyl cyclooctylideneacetate

To a suspension of 60% sodium hydride/mineral oil (969 mg) intetrahydrofuran (50 mL) was added ethyl diethylphosphonoacetate (5.48mL) dropwise under ice cooling. After stirring the solution under icecooling for 30 minutes, a solution of cyclooctanone (2.52 g) intetrahydrofuran (70 mL) was added dropwise to the solution under icecooling. The resulting solution was stirred under ice cooling for 2hours and at room temperature for 40 hours. Water and 3N hydrochloricacid were then added to the solution, and the mixture was extracted withdiethyl ether. The organic layer was washed with water and saturatedsodium chloride solution, dried over anhydrous magnesium sulfate, andthen, concentrated under reduced pressure. The resulting residue waspurified by chromatography (silica gel, hexane:ethyl acetate=9:1) togive the title compound (1.96 g).

¹H-NMR (CDCl₃) δ: 1.27 (t, 3H, J=7.2 Hz), 1.40-1.56 (m, 6H), 1.71-1.84(m, 4H), 2.72-2.79 (m, 2H), 4.13 (q, 2H, J=7.2 Hz), 5.72 (brs, 1H).

PREPARATION EXAMPLE 1A-2 2-Cyclooctylethanol

To a solution of ethyl cyclooctylideneacetate (969 mg) in ethanol (40mL) was added 10% palladium-carbon (60 mg). The solution was stirredunder hydrogen atmosphere at room temperature for 64 hours. The catalystwas filtered off and the filtrate was concentrated under reducedpressure. To a solution of the resulting residue (920 mg) in diethylether (40 mL) was added lithium aluminum hydride (132 mg) under icecooling. The solution was stirred under ice cooling for 30 minutes andthen water (0.13 mL), and a 15% aqueous sodium hydroxide solution (0.13mL) were successively added thereto. The solution was stirred at roomtemperature for 15 minutes, to which water (0.39 mL) was then added. Thesolution was stirred for additional 30 minutes, dried over anhydrousmagnesium-sulfate and concentrated under reduced pressure. The resultingresidue was purified by chromatography (silica gel, hexane:ethylacetate=2:1) to give the title compound (680 mg).

¹H-NMR (CDCl₃) δ: 1.16-1.36 (m, 3H), 1.38-1.74 (m, 14H), 3.67 (t, 2H,J=7.2 Hz).

PREPARATION EXAMPLE 1A-3 Cyclooctylacetaldehyde

To a solution of1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (490 mg) indichloromethane (3 mL) was added pyridine (0.25 mL). To the solution wasadded a solution of 2-cyclooctylethanol (120 mg) in dichlormethane (3mL) under ice cooling. The reaction solution was stirred at roomtemperature for 3 hours. To the solution was added diethyl ether, and itwas washed in turn with aqueous sodium thiosulfate, 1N hydrochloricacid, saturated aqueous sodium hydrogencarbonate and saturated aqueoussodium chloride. The solution was dried over anhydrous magnesium sulfateand concentrated under reduced pressure to give the title compound. Thisproduct was subjected to the subsequent step without furtherpurification.

PREPARATION EXAMPLE 1B-1 1,1-Cyclohexane diacetic acid anhydride

A solution of 1,1-cyclohexane diacetic acid (20.0 g) in acetic anhydride(20 mL) was heated under reflux for 5 hours. The solution wasconcentrated under reduced pressure, and the residue was concentratedthree times azeotropically with benzene. The resulting residue waspurified by column chromatography (silica gel, hexane:ethyl acetate=2:1)to give the title compound (20.1 g).

¹H-NMR (CDCl₃) δ: 1.42-1.57 (m, 10H), 2.65 (s, 4H).

PREPARATION EXAMPLE 1B-2 3-Oxa-spiro[5.5]undecan-2-one

To a solution of 1,1-cyclohexane diacetic acid anhydride (20.1 g) in THF(150 mL) was added sodium borohydride (3.78 g, 100 mmol) under icecooling. The reaction solution was stirred at room temperature foradditional 3 hours. Water was added to the solution, and it was madeacidic with conc. hydrochloric acid. The solution was extracted withethyl acetate. The organic layer was washed with water and saturatedaqueous sodium chloride solution, dried over anhydrous magnesium sulfateand filtered. The filtrate was then concentrated under reduced pressureto give the title compound (17.07 g). This product was subjected to thesubsequent step without further purification.

¹H-NMR (CDCl₃): 1.31-1.59 (m, 10H), 1.73 (t, 2H, J=6.1 Hz), 2.37 (s,2H), 4.32 (t, 2H, J=6.1 Hz).

PREPARATION EXAMPLE 1B-3 1-(2-Bromoethyl)cyclohexylacetic acid

To 3-oxa-spiro[5.5]undecan-2-one (16.9 g) was added a 30% hydrogenbromide/acetic acid solution (75 mL). The reaction solution was stirredat room temperature for 48 hours. Water was added to the solution, andthe crystals thus separated were recovered by filtration and washed withwater. The resulting crystals were dissolved in ethyl acetate, and thesolution was dried over anhydrous magnesium sulfate and filtered. Thefiltrate was then concentrated under reduced pressure to give crudecrystals. The crude crystals thus obtained were recrystallized fromethyl acetate-hexane to give the title compound (20.0 g).

¹H-NMR (CDCl₃) δ: 1.35-1.54 (m, 10H), 2.05-2.11 (m, 2H), 2.33 (s, 2H),3.41-3.47 (m, 2H).

PREPARATION EXAMPLE 1B-4 Methyl 1-(2-bromoethyl)cyclohexylacetate

To a solution of 1-(2-bromoethyl)cyclohexylacetic acid (4.98 g) inmethanol (50 mL) was added thionyl chloride (1.76 mL) dropwise under icecooling. After completion of the dropwise addition, the reactionsolution was stirred for 18 hours, while its temperature was allowed torise to room temperature. The reaction solution was concentrated underreduced pressure, and ethyl acetate was added to the resulting residue.The solution was washed in turn with saturated aqueous sodiumbicarbonate solution, water and saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and filtered. Thefiltrate was then concentrated under reduced pressure to give the titlecompound (5.41 g). This product was subjected to the subsequent stepwithout further purification.

¹H-NMR (CDCl₃) δ: 1.34-1.52 (m, 10H), 1.98-2.05 (m, 2H), 2.29 (s, 2H),3.41-3.46 (m, 2H), 3.67 (s, 3H).

PREPARATION EXAMPLE 1C-1 8-Oxa-spiro[4.5]undecan-7-one

Using 8-oxa-spiro[4.5]undecan-7,9-dione (10.8 g), the title compound(12.6 g) was prepared in the same manner as in Preparation Example 1B-2.This product was subjected to the subsequent step without furtherpurification.

PREPARATION EXAMPLE 1C-2 1-(2-Bromoethyl)cyclopentylacetic acid

Using 8-oxa-spiro[4.5]undecan-7-one (3.57 g), the title compound (0.87g) was prepared in the same manner as in

¹H-NMR (CDCl₃) δ: 1.51-1.67 (m, 8H), 2.08-2.12 (m, 2H), 2.34 (s, 2H),3.41-3.46 (m, 2H).

PREPARATION EXAMPLE 1C-3 Methyl 1-(2-bromoethyl)cyclopentylacetate

Using 1-(2-bromoethyl)cyclopentylacetic acid (2.20 g), the titlecompound (2.26 g) was prepared in the same manner as in PreparationExample 1B-4.

¹H-NMR (CDCl₃) δ 1.47-1.65 (m, 8H), 2.05 (t, 2H, J=8.3 Hz), 2.30 (s,3H), 3.43 (t, 2H, J=8.3 Hz), 3.67 (s, 3H).

PREPARATION EXAMPLE 1D-1 Methyl 1-allylcyclohexanecarboxylate

To a solution of methyl cyclohexylcarboxylate (1.42 g) and allyl bromide(3.02 g) in N,N-dimethylformamide (20 mL) was added potassiumtert-butoxide (1.68 g, 15.0 mmol) under ice cooling. The solution wasstirred at room temperature for 16 hours, at 50° C. for 8 hours andfurther at room temperature for 64 hours. Water and 3N hydrochloric acidwere then added to the solution, and it was extracted with diethylether. The extract was washed with water and saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (silica gel, hexane:ethyl acetate=97:3) to givethe title compound (340 mg).

PREPARATION EXAMPLE 1D-2 Methyl 1-(formylmethyl)cyclohexanecarboxylate

To a solution of methyl 1-allylcyclohexanecarboxylate (340 mg) intetrahydrofuran (7 mL) were added an aqueous solution of sodium periodicacid (3.4 g, 16.0 mmol) and osmium tetraoxide (100 mg) successivelyunder ice cooling. The solution was stirred at room temperature for 20hours. Water was added to the reaction solution and insolubles werefiltered off. The filtrate was extracted with ethyl acetate, and it waswashed in turn with water, sodium thiosulfate and saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give the title compound (250 mg).This product was subjected to the subsequent step without furtherpurification.

PREPARATION EXAMPLE 1E-1 Benzyl cyclohexanecarboxylate

To a solution of cyclohexanecarboxylic acid (2.56 g) in dichloromethane(50 ml) and N,N-dimethylformamide (0.5 mL) was added oxalyl chloride(1.92 mL) under ice cooling. The solution was stirred at roomtemperature for 1 hour and then concentrated under reduced pressure. Asolution of the resulting residue in dichloromethane (30 mL) was addedto a solution of benzyl alcohol (2.4 g) and triethylamine (8.4 mL) indichloromethane (30 mL) under ice cooling. The solution was stirredunder ice cooling for 1 hour, and then it was washed in turn with water,saturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution. The solution was dried over anhydrousmagnesium sulfate, and then, concentrated under reduced pressure. Theresulting residue was purified by column chromatography (silica gel,hexane:ethyl acetate=9:1) to give the title compound (3.44 g).

¹H-NMR (CDCl₃) δ: 1.17-1.34 (m, 3H), 1.40-1.53 (m, 2H), 1.60-1.68 (m,1H), 1.71-1.80 (m, 2H), 1.89-1.98 (m, 2H), 2.35 (tt, 1H, J=3.6 Hz, 11.2Hz), 5.11 (s, 2H), 7.26-7.41 (m, 5H).

PREPARATION EXAMPLE 1E-2 Benzyl 1-allylcyclohexanecarboxylate

To a solution of benzyl cyclohexanecarboxylate (1.44 g) intetrahydrofuran (40 mL) was added a 1M solution of lithiumhexamethyldisilazane in tetrahydrofuran (9.9 mL) under ice cooling. Thesolution was stirred at room temperature for 1 hour under ice cooling,to which hexamethylphosphoramide (2.3 mL) was added. The solution wasthen stirred for additional 10 minutes. To the solution was added allylbromide (1.4 mL). The solution was stirred under ice cooling for 1 hour,to which allyl bromide (1.4 mL) was further added. The solution wasstirred at room temperature for 18 hours. Water and 3N hydrochloric acidwere added to the solution, and it was extracted with diethyl ether. Theorganic layer was washed in turn with water, saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution. Thesolution was dried over anhydrous magnesium sulfate, and then,concentrated under reduced pressure. The resulting residue was purifiedby chromatography (silica gel, hexane:ethyl acetate=99:1) to give thetitle compound (550 mg). This product was subjected to the subsequentstep without further purification.

PREPARATION EXAMPLE 1E-3 Benzyl 1-(formylmethyl)cyclohexanecarboxylate

Using benzyl 1-allylcyclohexane carboxylate (1.52 g), the title compound(360 mg) was prepared in the same manner as in Preparation Example 1D-2.

¹H-NMR (CDCl₃) δ: 1.05-1.71 (m, 8H), 1.96-2.17 (m, 2H), 2.65 (d, 2H,J=2.0 Hz), 5.15 (s, 2H), 7.27-7.43 (m, 5H), 9.68 (t, 1H, J=2.0 Hz).

PREPARATION EXAMPLE 1F-1 3-Oxaspiro[5.5]undecan-2-ol

To a solution of 3-oxaspiro[5.5]undecan-2-one (1.68 g) in diethyl ether(50 mL) was added a 1M solution of diisobutylaluminum hydride in diethylether (15.0 mL) under ice cooling. The solution was stirred under icecooling for 15 minutes. Diethyl ether (100 mL) was then added to thesolution, followed by successive addition of water (0.6 mL) and a 15%aqueous sodium hydroxide solution (0.6 mL). The solution was stirred atroom temperature for 30 minutes. Water (1.8 mL) was then added to thesolution, and it was stirred for additional 15 minutes. The solution wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting residue was purified by column chromatography(silica gel, hexane:ethyl acetate=1:1) to give the title compound (1.36g).

¹H-NMR (CDCl₃) δ: 1.18-1.27 (m, 1H), 1.33-1.52 (m, 11H), 1.73-1.81 (m,1H), 3.15 (d, 1H, J=5.6 Hz), 3.60-3.69 (m, 1H), 3.86-3.93 (m, 1H),4.91-4.98 (m, 1H).

PREPARATION EXAMPLE 1F-2 Methyl 4-[1-(2-hydroxyethyl)cyclohexyl]butyrate

To a solution of 3-oxa-spiro[5.5]undecan-2-ol (460 mg) indichloromethane (15 mL) was added methyltriphenylphosphoranylideneacetate (1.36 g). After stirring the solutionunder reflux for 3 hours, methyl triphenylphosphoranylideneacetate (1.36g) was further added thereto. The solution was stirred under reflux for14 hours. The solution was concentrated under reduced pressure, and theresulting residue was purified by chromatography (silica gel,hexane:ethyl acetate=1:1) to give a mixture of an unsaturated esterderivative and 3-oxa-spiro[5.5]undecan-2-ol (520 mg). To a solution ofthe resulting mixture in ethanol (30 mL) was added 10% palladium-carbon(60 mg). The mixture was stirred at room temperature under hydrogenatmosphere for 63 hours. The catalyst was filtered off, concentratedunder reduced pressure and the resulting residue was purified bychromatography (silica gel, hexane:ethyl acetate=1:1) to give the titlecompound (210 mg).

¹H-NMR (CDCl₃) δ: 1.23-1.48 (m, 12H), 1.52-1.68 (m, 4H), 2.29 (t, 2H,J=7.2 Hz), 3.62-3.71 (m, 2H), 3.67 (s, 3H).

PREPARATION EXAMPLE 1F-3 Methyl 4-[1-(formylmethyl)cyclohexyl]butyrate

Using methyl 4-[1-(2-hydroxyethyl)cyclohexyl]butyrate (210 mg), thetitle compound (220 mg) was prepared in the same manner as inPreparation Example 1A-3. This product was subjected to the subsequentstep without further purification.

¹H-NMR (CDCl₃) δ: 1.21-1.69 (m, 14H), 2.26-2.37 (m, 4H), 3.67 (s, 3H),9.85 (t, 1H, J=3.2 Hz).

PREPARATION EXAMPLE 1G-1 (1-Allylcyclohexyl)methanol

To a solution of cyclohexane carbaldehyde (2.24 g) inN,N-dimethylformamide (30 mL) were added potassium tert-butoxide (2.70g) and allyl bromide (4.33 mL) under ice cooling. The solution wasstirred under ice cooling for 30 minutes. Water and 1N hydrochloric acidwere then added to the solution, and it was extracted with diethylether. The organic layer was washed with water and saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. To a solution of the resultingresidue in ethanol (60 mL) was added sodium borohydride (567 mg) underice cooling. The solution was stirred at room temperature for 16 hours.Acetic acid was added to the solution, and it was concentrated underreduced pressure. To the resulting residue was added saturated aqueoussodium bicarbonate solution, and it was extracted with diethyl ether.The organic layer was washed in turn with water and saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (silica gel, hexane:ethyl acetate=4:1) to givethe title compound (1.47 g).

¹H-NMR (CDCl₃) δ: 1.21-1.55 (m, 10H), 2.01-2.24 (m, 2H), 3.31-3.54 (m,2H), 5.02-5.12 (m, 2H), 5.81-5.93 (m, 1H).

PREPARATION EXAMPLE 1G-2 [1-(Allylcyclohexyl)methoxy]triethylsilane

To a solution of (1-allylcyclohexyl)methanol (1.0 g) inN,N-dimethylformamide (7 mL) were added imidazole (661 mg) andtriethylchlorosilane (1.41 mL) at room temperature. After stirring thesolution at room temperature for 3 hours, N,N-dimethylformamide wasadded thereto and it was extracted with hexane. The combined hexanelayer was washed with acetonitrile and concentrated under reducedpressure to give the title compound (1.70 g). This product was subjectedto the subsequent step without further purification.

PREPARATION EXAMPLE 1G-33-[1-(Triethylsiloxymethyl)cyclohexyl]propan-1-ol

To a solution of [1-(allylcyclohexyl)methoxy]triethylsilane (1.70 g) intetrahydrofuran (35 mL) were added a 2M borane-methyl sulfide complexsolution in tetrahydrofuran (6.48 mL, 12.96 mmol) under ice cooling. Thesolution was stirred under ice cooling for 2 hours. To this were thenadded water, a 3N aqueous sodium hydroxide solution (6.5 mL) and 30%hydrogen peroxide (6.5 mL). The solution was stirred at room temperaturefor 16 hours. Water was added and the solution was extracted with ethylacetate. The organic layer was washed in turn with water and saturatedaqueous sodium chloride solution, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The resulting residue waspurified by column chromatography (silica gel, hexane:ethyl acetate=7:3)to give the title compound (810 mg).

¹H-NMR (CDCl₃) δ: 0.58 (q, 6H, J=8.0 Hz), 0.95 (t, 9H, J=8.0 Hz),1.22-1.61 (m, 15H), 3.35 (s, 2H), 3.56-3.66 (m, 2H).

PREPARATION EXAMPLE 1G-4[1-(3-Acetoxypropyl)cyclohexylmethoxy]triethylsilane

To 3-[1-(triethylsiloxymethyl)cyclohexyl]propan-1-ol (410 mg) were addedacetic anhydride (3 mL) and pyridine (3 mL) at room temperature. Thesolution was stirred at room temperature for 2 hours and concentratedunder reduced pressure. The residue was distilled with tolueneazeotropically to give the title compound (480 mg). This product wassubjected to the subsequent step without further pirification.

¹H-NMR (CDCl₃) δ: 0.57 (q, 6H, J=7.6 Hz), 0.95 (t, 9H, J=7.6 Hz),1.20-1.46 (m, 12H), 1.49-1.60 (m, 2H), 2.04 (s, 3H), 3.33 (s, 2H), 4.03(t, 2H, J=6.8 Hz).

PREPARATION EXAMPLE 1G-5 3-(1-Hydroxymethylcyclohexyl)propyl acetate

Using benzyl [1-(3-acetoxypropyl)cyclohexylmethoxy]triethylsilane (480mg), the title compound (310 mg) was prepared in the same manner as inPreparation Example 3B-2.

¹H-NMR (CDCl₃) δ: 1.21-1.50 (m, 12H), 1.53-1.71 (m, 2H), 2.05 (s, 3H),3.43 (s, 2H), 4.05 (t, 2H, J=7.2 Hz).

PREPARATION EXAMPLE 1H-1[N-(tert-Butoxycarbonyl)-N-carboxymethylamino]acetic acid

Iminodiacetic acid (10.00 g) was dissolved in a mixed solution of1,4-dioxane (160 mL) and water (80 mL). To this were added a 1N aqueoussodium hydroxide solution (160 mL) and then di-tert-butyl dicarbonate(18.04 g). The solution was stirred at room temperature for 22 hours.The solution was concentrated under reduced pressure, made to pH 3 byaddition of a 5% potassium hydrogen sulfate solution and then extractedwith 25% ethanol/chloroform. The extract was dried over anhydrousmagnesium sulfate and the solvent was distilled off under reducedpressure. The resulting residue was washed with hexane to give the titlecompound (4.25 g).

¹H-NMR (DMSO-d₆) δ: F1.37 (s, 9H), 3.88 (s, 2H), 3.91 (s, 2H).

PREPARATION EXAMPLE 1H-2 Ethyl[({tert-butoxycarbonyl-[(diethoxycarbonylmethylcarbamoyl)methyl]amino}acetyl)ethoxycarbonylmethylamino]acetate

To a solution of [N-(tert-butoxycarbonyl)-N-carboxymethylamino]aceticacid (0.57 g) dissolved in dichloromethane (5 mL) were addediminodiacetic acid diethyl ester (1.40 g), N,N-diisopropylethylamine(1.59 g) and then 2-bromo-1-ethylpyridinium tetrafluoroborate (1.95 g).The solution was stirred at room temperature for 1 hour. Ethyl acetatewas added to the solution and it was washed in turn with saturatedaqueous sodium bicarbonate solution and saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate and thesolvent was distilled off under reduced pressure. The resulting residuewas purified by column chromatography (silica gel, 5-10%methanol/dichloromethane) to give the title compound (0.79 g).

¹H-NMR (DMSO-d₆) δ: 1.17-1.24 (m, 12H), 1.35 (s, 9H), 3.96-4.26 (m,20H).

PREPARATION EXAMPLE 1H-3 Ethyl[({[diethoxycarbonylmethylcarbamoyl)methyl]amino}acetyl)ethoxycarbonylmethylamino]acetatetrifluoroacetic acid salt

To a solution of ethyl[({tert-butoxycarbonyl-[(diethoxycarbonylmethylcarbamoyl)methyl]amino}acetyl)ethoxycarbonylmethylamino]acetate(0.79 g) dissolved in dichloromethane (8 mL) was added trifluoroaceticacid (8.0 mL) at room temperature. The solution was stirred for 2 hours.The solvent was distilled off under reduced pressure and then, theresidue was distilled with xylene azeotropically to give the titlecompound (0.81 g). This product was subjected to the subsequent stepwithout further purification.

PREPARATION EXAMPLE 1I-1 2-Acetoxymethyl-2-amino-1,3-diacetoxypropane

To 2-amino-2-hydroxymethyl-1,3-propanediol (10.00 g) were added aceticacid (40.0 mL), 1N hydrochloric acid/diethyl ether solution (90.0 mL)and acetic anhydride (30.0 mL) successively. The solution was heatedunder reflux at 110° C. for 6 hours. The solvent was distilled off underreduced pressure, and distilled to dryness with xylene azeotropically.The resulting residue was diluted with water, washed with ethyl acetate,the aqueous layer was made to pH 8 with sodium hydrogencarbonate, and itwas then extracted with 25% ethanol/chloroform. The organic layer wasdried over anhydrous magnesium sulfate and the solvent was distilled offunder reduced pressure. The resulting residue was purified by columnchromatography (silica gel, 3-4% ethanol/dichloromethane) to give thetitle compound (4.02 g).

¹H-NMR (DMSO-d₆) δ: 2.02 (s, 9H), 3.24 (brs, 2H), 3.94 (s, 6H).

PREPARATION EXAMPLE 1J-13-Acetoxy-2-(2-{[(2-acetoxy-1,1-diacetoxymethylethylcarbamoyl)methyl]amino}acetylamino)-2-acetoxymethylpropylacetate

To a solution of 2-acetoxymethyl-2-amino-1,3-diacetoxypropane (1.18 g)dissolved in dichloromethane (8 mL) were added[N-(tert-butoxycarbonyl)-N-carboxymethyl]acetic acid (0.56 g),N,N-diiospropylethylamine (1.54 g) and then2-bromo-1-ethylpyridiniumtetrafluoroborate (1.96 g). The solution wasstirred at room temperature for 10 hours. After addition of ethylacetate, the solution was washed in turn with a 5% aqueous potassiumhydrogensulfate solution, saturated aqueous sodium bicarbonate solutionand saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resulting residue was purified by column chromatography(silica gel, 5-10% methanol/dichloromethane). The resulting compound wasdissolved in dichloromethane (5 mL), to which trifluoroacetic acid (5.0mL) was added at room temperature. The solution was stirred for 16hours. The solvent was distilled off under reduced pressure. Theresulting residue was purified by column chromatography [silica gel,dichloromethane-methanol-aqueous ammonia(90:10:0.5)] to give the titlecompound (0.47 g). This product was subjected to the subsequent stepwithout further purification.

¹H-NMR (DMSO-d₆) δ: 1.82 (s, 6H), 2.01 (s, 12H), 3.48-3.53 (m, 4H),4.25-4.31 (m, 8H), 4.33-4.38 (m, 4H).

PREPARATION EXAMPLE 1K-1 1-Methoxycarbonylmethylcyclohexylacetic acid

A solution of 1,1-cyclohexanediacetic acid (5.0 g) in acetic anhydride(8.0 mL) was stirred under reflux for 5 hours. The solution was thenconcentrated under reduced pressure and distilled with tolueneazeotropically. To a solution of the resulting residue in methanol (15.2mL) was added boron trifluoride diethyl ether complex (1.58 mL) at roomtemperature. The solution was stirred at room temperature for 2 hours.Saturated aqueous sodium carbonate solution was added to the solutionand it was washed with diethyl ether. The aqueous layer was neutralizedby addition of conc. hydrochloric acid and then extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride solution, and then, dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure to give the titlecompound (4.21 g).

¹H-NMR (CDCl₃) δ: 1.38-1.60 (m, 10H), 2.56 (s, 2H), 2.58 (s, 2H), 3.68(s, 3H).

PREPARATION EXAMPLE 1K-2 1-Methoxycarbonylmethylcyclohexylacetic acid

To a solution of 1-methoxycarbonylmethylcyclohexylacetic acid (265 mg)in a mixed solvent of methylene chloride (10 mL) andN,N-dimethylformamide (one drop) was added oxalyl chloride (0.12 mL)under ice cooling. After stirring the solution at room temperature for 1hour, it was concentrated under reduced pressure to give the titlecompound. This product was subjected to the subsequent step withoutfurther purification.

PREPARATION EXAMPLE 2A-1 Ethyl 3-(2-nitrophenyl)acrylate

To a suspension of 60% sodium hydride/mineral oil (1.11 g) intetrahydrofuran (40 mL) was added ethyl diethylphosphonoacetate (6.29mL) dropwise under ice cooling. After stirring the mixture under icecooling for 30 minutes, a solution of 2-nitrobenzaldehyde (3.0 g) intetrahydrofuran (30 mL) was added thereto under ice cooling. Thesolution was stirred at room temperature for 8 hours. Water and 3Nhydrochloric acid were then added to the solution and it was extractedwith diethyl ether. The organic layer was washed with water andsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingresidue was purified by column chromatography (silica gel, hexane:ethylacetate=3:2) to give the title compound (3.74 g).

¹H-NMR (CDCl₃) δ: 1.35 (t, 3H, J=6.8 Hz), 4.29 (q, 2H, J=6.8 Hz), 6.36(d, 1H, J=16.0 Hz), 7.50-7.59 (m, 1H), 7.61-7.69 (m, 2H), 8.04 (d, 1H,J=8.8 Hz), 8.12 (d, 1H, J=16.0 Hz).

PREPARATION EXAMPLE 2A-2 3-(2-Aminophenyl)propan-1-ol

To a solution of ethyl 3-(2-nitrophenyl)acrylate (1.11 g) in diethylether (30 mL) was added a 1M diisobutylaluminum hydride solution inhexane (15.0 mL) under ice cooling. After stirring the solution underice cooling for 1 hour, diethyl ether, water (0.6 mL) and a 15% aqueoussodium hydroxide solution (0.6 mL) were added thereto. The solution wasstirred at room temperature for 15 minutes. Water (1.8 mL) was thenadded and the solution was stirred at room temperature for 15 minutes.Anhydrous magnesium sulfate was added to the solution and filtered. Thefiltrate was concentrated under reduced pressure. To a solution of theresulting residue in ethanol (50 mL) was added 10% palladium-carbon (200mg). The mixture was stirred at room temperature under hydrogenatmosphere for 89 hours. The catalyst was filtered off, and the filtratewas concentrated under reduced pressure. The resulting residue waspurified by column chromatography (silica gel, hexane:ethyl acetate=1:2)to give the title compound (660 mg).

¹H-NMR (CDCl₃) δ: 1.81-1.95 (m, 2H), 2.64 (t, 2H, J=7.2 Hz), 3.64 (t,2H, J=5.2 Hz), 6.69 (d, 1H, J=7.6 Hz), 6.73-6.79 (m, 1H), 7.00-7.08 (m,2H).

PREPARATION EXAMPLE 2A-32-Cyclohexyl-N-[2-(3-hydroxypropyl)phenyl]acetamide

To a solution of 3-(2-aminophenyl)propan-1-ol (180 mg) andcyclohexylacetic acid (203 mg) in dichloromethane (12 mL) were added1-hydroxybenzotriazole (193 mg) and1-ethyl-1-(1-dimethylaminopropyl)carbodiimide hydrochloride (274 mg)under ice cooling. The solution was stirred at room temperature for 113hours. Chloroform was then added to the solution and it was washed inturn with water and saturated aqueous sodium bicarbonate solution, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The resulting residue was purified by column chromatography (silica gel,hexane:ethyl acetate=1:1) to give the title compound (170 mg).

¹H-NMR (CDCl₃) δ: 0.93-1.08 (m, 2H), 1.08-1.22 (m, 1H), 1.22-1.36 (m,2H), 1.56-2.06 (m, 8H), 2.22 (d, 2H, J=7.2 Hz), 2.75 (t, 2H, J=6.8 Hz),3.60 (t, 2H, J=5.6 Hz), 7.03-7.12 (m, 1H), 7.13-7.25 (m, 2H), 7.88 (d,1H, J=7.6 Hz), 8.36 (brs, 1H).

PREPARATION EXAMPLE 2A-42-Cyclohexyl-N-[2-(2-formylethyl)phenyl]acetamide

The title compound was synthesized from the compound obtained inPreparation Example 2A-3 in the same manner as in Preparation Example1A-3.

PREPARATION EXAMPLE 2B-12-Cyclohexyl-N-[2-(2-hydroxyethyl)phenyl]acetamide

Using 2-aminophenethyl alcohol (500 m), the title compound (780 mg) wasobtained in the same manner as in Preparation Example 2A-3.

¹H-NMR (CDCl₃) δ: 0.94-1.09 (m, 2H), 1.10-1.36 (m, 3H), 1.52-1.96 (m,6H), 2.22 (d, 2H, J=8.4 Hz), 2.84 (t, 2H, J=5.2 Hz), 3.97 (t, 2H, J=5.2Hz), 7.05-7.12 (m, 1H), 7.13-7.18 (m, 1H), 7.21-7.29 (m, 1H), 7.82-7.89(m, 1H), 8.78 (brs, 1H).

PREPARATION EXAMPLE 2B-2N-[2-(2-Bromoethyl)phenyl]-2-cyclohexylacetamide

To a solution of 2-cyclohexyl-N-[2-(2-hydroxyethyl)phenyl]acetamide (780mg) in dichloromethane (20 mL) were added triphenylphosphine (938 mg)and carbon tetrabromide (1.12 g) at room temperature. The solution wasstirred at room temperature for 1 hour. Chloroform was added and thesolution was washed in turn with water and saturated aqueous sodiumbicarbonate solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (silica gel, hexane:ethyl acetate=7:3) to givethe title compound (450 mg).

¹H-NMR (CDCl₃) δ: 0.97-1.39 (m, 5H), 1.64-1.80 (m, 3H), 1.80-1.97 (m,3H), 2.27 (d, 2H, J=6.8 Hz), 3.16 (t, 2H, J=7.2 Hz), 3.59 (t, 2H, J=7.2Hz), 7.14-7.33 (m, 4H), 7.57-7.64 (m, 1H).

PREPARATION EXAMPLE 2C-1 1-(2-Bromoethyl)-2-nitrobenzene

Using 1-(2-hydroxyethyl)-2-nitrobenzene (10.11 g), the title compound(21.46 g) was obtained in the same manner as in Preparation Example2B-2. This product was subjected to the subsequent step without furtherpurification.

¹H-NMR (CDCl₃) δ: 3.46 (t, 2H, J=7.3 Hz), 3.68 (t, 2H, J=7.3 Hz),7.41-7.46 (m, 2H), 7.55-7.60 (m, 1H), 7.97-8.00 (m, 1H).

PREPARATION EXAMPLE 2D-1 1-(3-Hydroxy-1-propenyl)-2-nitrobenzene

To a solution of 2-trans-nitrocinnamaldehyde (10.00 g) dissolved inethanol (50 mL) was added sodium borohydride (2.14 g) under ice cooling.The reaction solution was stirred for 1 hour. The reaction solution waspoured into saturated aqueous sodium bicarbonate solution, and it wasextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and the solvent was distilled off under reducedpressure. The resulting residue was purified by column chromatography(silica gel, 20-50% ethyl acetate/hexane) to give the title compound(8.00 g).

¹H-NMR (CDCl₃) δ: 1.64 (t, 1H, J=5.9 Hz), 4.38 (ddd, 2H, J=2.0 Hz, 5.4Hz, 5.9 Hz), 6.34 (dt, 1H, J=15.6 Hz, 5.4 Hz), 7.10 (dt, 1H, J=15.6 Hz,2.0 Hz), 7.37-7.42 (m, 1H), 7.53-7.62 (m, 2H), 7.90-7.93 (m, 1H).

PREPARATION EXAMPLE 2D-2 1-(3-Bromo-1-propenyl)-2-nitrobenzene

Using 1-(3-hydroxy-1-propenyl)-2-nitrobenzene (8.00 g), the titlecompound (17.1 g) was obtained in the same manner as in PreparationExample 2B-2. This product was subjected to the subsequent step withoutfurther purification.

PREPARATION EXAMPLE 2E-1 tert-Butyl 2-(3-hydroxypropyl)phenylcarbamate

To a solution of 3-(2-aminophenyl)propan-1-ol (660 mg) intetrahydrofuran (10 mL) were added triethylamine (1.52 mL) anddi-tert-butyl dicarbonate (1.91 g) under ice cooling. The solution wasstirred at room temperature for 20 hours. Ethyl acetate and water wereadded to carry out extraction. The organic layer was washed in turn with1N hydrochloric acid, saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingresidue was purified by column chromatography (silica gel, hexane:ethylacetate=60:40) to give the title compound (730 mg).

¹H-NMR (CDCl₃) δ: 1.51 (s, 9H), 1.82-19.2 (m, 2H), 2.73 (t, 2H, J=6.8Hz), 3.59-3.67 (m, 2H), 7.00-7.07 (m, 1H), 7.11-7.23 (m, 3H), 7.75 (brd,1H, J=8.0 Hz).

PREPARATION EXAMPLE 2E-2 tert-Butyl 2-(3-Bromopropyl)phenylcarbamate

Using tert-butyl 2-(3-hydroxypropyl)phenylcarbamate (730 mg), the titlecompound (670 mg) was obtained in the same manner as in PreparationExample 2B-2.

¹H-NMR (CDCl₃): 1.52 (s, 9H), 2.09-2.19 (m, 2H), 2.76 (t, 2H, J=7.2 Hz),3.44 (t, 2H, J=6.4 Hz), 6.38 (brs, 1H), 7.01-7.08 (m, 1H), 7.13-7.25 (m,2H), 7.74 (brd, 1H, J=8.4 Hz).

PREPARATION EXAMPLE 2F-1 tert-Butyl 2-(2-hydroxyethyl)phenylcarbamate

Using 2-aminophenethyl alcohol (1.0 g), the title compound (1.14 g) wasobtained in the same manner as in Preparation Example 2E-1.

¹H-NMR (CDCl₃) δ: 1.51 (s, 9H), 1.95-2.05 (m, 1H), 2.84 (t, 2H, J=5.6Hz), 3.88-3.94 (m, 2H), 7.01-7.08 (m, 1H), 7.11-7.17 (m, 1H), 7.19-7.26(m, 1H), 7.55-7.65 (m, 1H), 7.68-7.76 (m, 1H).

PREPARATION EXAMPLE 2F-2 tert-Butyl 2-(2-bromoethyl)phenylcarbamate

Using tert-butyl 2-(2-hydroxyethyl)phenylcarbamate (1.14 g), the titlecompound (0.75 g) was obtained in the same manner as in PreparationExample 2B-2.

¹H-NMR (CDCl₃) δ: 1.52 (s, 9H), 3.16 (t, 2H, J=7.2 Hz), 3.58 (t, 2H,J=7.2 Hz), 6.37 (brs, 1H), 7.08-7.15 (m, 1H), 7.16-7.21 (m, 1H),7.23-7.29 (m, 1H), 7.63 (brd, 1H, J=8.0 Hz).

PREPARATION EXAMPLE 3A-1 2-[1-(2-Hydroxyethyl)cyclohexyl]ethanol

To a solution of 1,1,-cyclohexanediacetic acid (6.0 g) intetrahydrofuran (90 mL) was added lithium aluminum hydride (2.28 g)under ice cooling. The solution was stirred under reflux for 4 hours,and then, cooled on ice, to which diethyl ether (200 mL), water (2.3 mL)and a 15% aqueous sodium hydroxide solution (2.3 mL) were added. Afterstirring the solution at room temperature for 30 minutes, water (6.9 mL)was added and the solution was stirred at room temperature foradditional 30 minutes. Anhydrous magnesium sulfate was added to thesolution, and it was filtered under reduced pressure. The filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby chromatography (silica gel, ethyl acetate) to give the title compound(4.83 g).

¹H-NMR (CDCl₃) δ: 1.23-1.50 (m, 10H), 1.64 (t, 4H, J=7.2 Hz), 1.96-2.17(m, 2H), 3.72 (t, 4H, J=7.2 Hz).

PREPARATION EXAMPLE 3A-22-[1-[2-(tert-Butyldiphenylsiloxy)ethyl]cyclohexyl]ethanol

To a solution of 2-[1-(2-hydroxyethyl)cyclohexyl]ethanol (6.41 g) indichloromethane (170 mL) were added triethylamine (6.74 mL) andtert-butyldiphenylchlorosilane (11.1 mL) at room temperature. Afterstirring the solution at room temperature for 18 hours, chloroform wasadded to the solution, and it was washed in turn with 1N hydrochloricacid, saturated aqueous sodium bicarbonate solution and saturatedaqueous sodium chloride solution. The solution was dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by chromatography (silica gel,hexane:ethyl acetate=85:15) to give the title compound (10.97 g).

¹H-NMR (CDCl₃) δ: 1.05 (s, 9H), 1.19-1.43 (m, 10H), 1.48-1.55 (m, 3H),1.61 (t, 2H, J=7.6 Hz), 3.56 (t, 2H, J=7.6 Hz), 3.70 (t, 2H, J=7.6 Hz),7.35-7.47 (m, 6H), 7.64-7.73 (m, 4H).

PREPARATION EXAMPLE 3A-3 tert-Butyl[2-[1-(2-iodoethyl)cyclohexyl]ethoxy]diphenylsilane

To a solution of 2-[1-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethanol(4.0 g) in tetrahydrofuran (60 mL) and acetonitrile (20 mL) were addedtriphenylphosphine (3.3 mL), imidazole (993 mg) and iodine (3.46 g) atroom temperature successively. After stirring the solution at roomtemperature for 2 hours, diethyl ether was added to the solution, and itwas washed in turn with an aqueous sodium thiosulfate solution, water,and saturated aqueous sodium chloride solution. The solution was driedover anhydrous magnesium sulfate, and then, concentrated under reducedpressure. The resulting residue was dissolved in acetonitrile. Thesolution was extracted with hexane. The combined hexane layer was washedwith acetonitrile and concentrated under reduced pressure to give thetitle compound (4.83 g).

¹H-NMR (CDCl₃) δ: 1.05 (s, 9H), 1.16-1.41 (m, 8H), 1.49-1.56 (m, 4H),1.85-1.93 (m, 2H), 2.94-3.04 (m, 2H), 3.66 (t, 2H, J=7.6 Hz), 7.35-7.47(m, 6H), 7.63-7.71 (m, 4H).

PREPARATION EXAMPLE 3A-4 Triethyl3-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]-1,1,1-propanetricarboxylate

To a solution of tert-butyl[2-[1-(2-iodoethyl)cyclohexyl]ethoxy]diphenylsilane (540 mg) and ethylmethane tricarboxylate (727 mg) in N,N-dimethylformamide (5 mL) wasadded potassium carbonate (575 mg) at room temperature. The solution wasstirred at 110° C. for 6 hours, to which water and 3N hydrochloric acidwere added. The solution was extracted with ethyl acetate. The organiclayer was washed in turn with a 1N aqueous sodium hydroxide solution,water and saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting residue was purified by chromatography (silica gel,hexane:ethyl acetate=85:15) to give the title compound (470 mg).

¹H-NMR (CDCl₃) δ: 1.03 (s, 9H), 1.17-1.40 (m, 12H), 1.23 (t, 9H, J=6.8Hz), 1.60 (t, 2H, J=8.0 Hz), 1.96-2.04 (m, 2H), 3.68 (t, 2H, J=8.0 Hz),4.18 (q, 6H, J=6.8 Hz), 7.73-7.45 (m, 6H), 7.64-7.70 (m, 4H).

PREPARATION EXAMPLE 3A-5 Triethyl3-[1-(2-hydroxyethyl)cyclohexyl]-1,1,1-propanetricarboxylate

To a solution of triethyl3-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]-1,1,1-propanetricarboxylate(470 mg) in methanol (10 mL)/tetrahydrofuran (5 mL) was added 3Nhydrochloric acid (2.5 mL) at room temperature. After stirring thesolution at room temperature for 4 hours, water was added to thesolution, and it was concentrated under reduced pressure. The solutionwas extracted with ethyl acetate. The organic layer was washed in turnwith water and saturated aqueous sodium chloride solution. The solutionwas dried over anhydrous magnesium sulfate, and then, concentrated underreduced pressure. The resulting residue was purified by chromatography(silica gel, hexane:ethyl acetate=1:1) to give the title compound (230mg).

¹H-NMR (CDCl₃) δ: 1.23-1.51 (m, 12H), 1.29 (t, 9H, J=7.2 Hz), 1.56-1.64(m, 2H), 2.03-2.11 (m, 2H), 3.68 (t, 2H, J=7.2 Hz), 4.26 (q, 6H, J=7.2Hz).

PREPARATION EXAMPLE 3A-6 Triethyl3-[1-(formylmethyl)cyclohexyl]-1,1,1-propanetricarboxylate

To a solution of triethyl3-[1-(2-hydroxyethyl)cyclohexyl]-1,1,1-propanetricarboxylate (230 mg) indichloromethane (6 mL) were added diacetic acid iodobenzene (213 mg) and2,2,6,6-tetramethyl-1-piperidinyloxy free radical (9.3 mg) at roomtemperature. The solution was stirred at room temperature for 16 hours.Diethyl ether was added to the solution, and it washed in turn with anaqueous sodium thiosulfate solution, 1N hydrochloric acid, saturatedaqueous sodium bicarbonate solution and saturated aqueous sodiumchloride solution. The solution was dried over anhydrous magnesiumsulfate, and then, concentrated under reduced pressure to give the titlecompound. This product was subjected to the subsequent step withoutfurther purification.

PREPARATION EXAMPLE 3B-1 Dimethyl3-[1-[(2-tert-butyldiphenylsiloxy)ethyl]cyclohexyl]-1,1-pro-panedicarboxylate

To a solution of tert-butyl2-[1-(2-iodoethyl)cyclohexyl]ethoxy]diphenylsilane (1.5 g) and dimethylmalonate (1.90 g) in N,N-dimethylformamide (20 mL) was added potassiumtert-butoxide (1.45 g) at room temperature. After stirring the solutionat 60° C. for 4 hours, water and 3N hydrochloric acid were added to thesolution, and it was extracted with ethyl acetate. The combined organiclayer was washed in turn with water and saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, and then,concentrated under reduced pressure. The resulting residue was purifiedby chromatography (silica gel, hexane:ethyl acetate=9:1) to give thetitle compound (1.32 g).

¹H-NMR (CDCl₃) δ: 1.04 (s, 9H), 1.11-1.38 (m, 11H), 1.51-1.63 (m, 3H),1.71-1.80 (m, 2H), 3.19 (t, 1H, J=8.0 Hz), 3.65 (t, 2H, J=8.0 Hz), 3.69(s, 6H), 7.34-7.44 (m, 6H), 7.64-7.71 (m, 4H).

PREPARATION EXAMPLE 3B-2 Dimethyl3-[1-(2-hydroxyethyl)cyclohexyl]-1,1-propanedicarboxylate

To a solution of dimethyl3-[1-(2-(tert-butyldiphenylsiloxy)ethyl)cyclohexyl]-1,1-pro-panedicarboxylate(500 mg) in tetrahydrofuran (10 mL) was added a 1M tetrabutylammoniumfluoride/tetrahydrofuran solution (1.9 mL) at room temperature. Thesolution was stirred at room temperature for 3 hours. Water was added tothe solution, and it was extracted with ethyl acetate. The organic layerwas washed in turn with an aqueous ammonium chloride solution, andsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and then, concentrated under reduced pressure. Theresulting residue was purified by chromatography (silica gel,hexane:ethyl acetate=11:1) to give the title compound (180 mg).

¹H-NMR (CDCl₃) δ: 1.21-1.49 (m, 12H), 1.55-1.68 (m, 2H), 1.80-1.91 (m,2H), 3.30 (t, 1H, J=7.6 Hz), 3.66 (t, 2H, J=7.6 Hz), 3.75 (s, 6H).

PREPARATION EXAMPLE 3B-3 Dimethyl2-{2-[1-(formylmethyl)cyclohexyl]ethyl}malonate

Using dimethyl 3-[1-(2-hydroxyethyl)cyclohexyl]-1,1-propanedicarboxylate(180 mg), the crude title compound was obtained in the same manner as inPreparation Example 3A-6. This product was subjected to the subsequentstep without further purification.

PREPARATION EXAMPLE 3C-12-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethyl-propane-1,3-diol

To a solution of dimethyl3-[1-(2-(tert-butyldiphenylsiloxy)ethyl)cyclohexyl]-1,1-pro-panedicarboxylate(1.32 g) in diethyl ether (30 mL) was added lithium aluminum hydride(191 mg) under ice cooling. After stirring the solution under icecooling for 2 hours, water (0.2 mL) and a 15% aqueous sodium hydroxidesolution (0.2 mL) were successively added to the solution. The solutionwas stirred at room temperature for 15 minutes. Water (0.6 mL) was thenadded to the solution, and it was stirred for additional 30 minutes. Thesolution was dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The resulting residue was purified bychromatography (silica gel, hexane:ethyl acetate=1:1) to give the titlecompound (790 mg).

¹H-NMR (CDCl₃) δ: 1.04 (s, 9H), 1.11-11.41 (m, 11H), 1.50-1.61 (m, 5H),1.99-2.08 (m, 1H), 3.54 (dd, 2H, J=7.6 Hz, 9.4 Hz), 3.65 (t, 2H, J=7.6Hz), 3.70 (dd, 1H, J=4.6 Hz, 9.6 Hz), 7.34-7.46 (m, 6H), 7.63-7.73 (m,4H).

PREPARATION EXAMPLE 3C-22-[2-[1-(2-Hydroxyethyl)cyclohexyl]ethyl]-1,3-diacetoxypropane

To a solution of2-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethyl]propane-1,3-diol(190 mg) in pyridine (3.0 mL) was added acetic anhydride (3.0 mL) atroom temperature. After stirring the solution at room temperature for 3hours, it was concentrated under reduced pressure. To a solution of theresulting residue in tetrahydrofuran (8 mL) was added a 1Mtetrabutylammonium bromide/tetrahydrofuran solution (0.53 mL) at roomtemperature. The solution was stirred at room temperature for 1 hour, towhich a 1M tetrabutylammonium bromide/tetrahydrofuran solution (0.53 mL)was further added at room temperature. The solution was stirred at roomtemperature for 1 hour, to which a 1M tetrabutylammoniumbromide/tetrahydrofuran solution (0.53 mL) was still further added atroom temperature. The solution was stirred at room temperature for 1hour and water was added thereto, and it was extracted with ethylacetate. The organic layer was washed in turn with saturated aqueousammonium chloride solution and saturated aqueous sodium chloridesolution. The solution was dried over anhydrous magnesium sulfate, andthen, concentrated under reduced pressure. The resulting residue waspurified by chromatography (silica gel, hexane:ethyl acetate=1:1) togive the title compound (140 mg).

¹H-NMR (CDCl₃) δ: 1.19-1.35 (m, 8H), 1.36-1.49 (m, 5H), 1.53-1.65 (m,3H), 1.87-1.96 (m, 1H), 2.06 (s, 6H), 3.64 (t, 2H, J=8.0 Hz), 4.05 (dd,2H, J=6.4 Hz, 11.2 Hz), 4.09 (dd, 2H, J=4.8 Hz, 11.2 Hz).

PREPARATION EXAMPLE 3C-32-[2-[1-(Formylmethyl)cyclohexyl]ethyl]-1,3-diacetoxypropane

Using 2-[2-[1-(2-hydroxyethyl)cyclohexyl]ethyl]-1,3-diacetoxypropane(140 mg), the title compound (117 mg) was obtained in the same manner asin Preparation Example 1A-3. This product was subjected to thesubsequent step without further purification.

PREPARATION EXAMPLE 3D-1 2-[1-(2-Benzyloxyethyl)cyclohexyl]ethanol

To a suspension of 60% sodium hydride/mineral oil (881 mg) inN,N-dimethylformamide (20 mL) was added2-[1-(2-hydroxyethyl)cyclohexyl]ethanol (2.92 g) under ice cooling. Tothe solution was further added benzyl bromide (2.83 mL) under icecooling, and it was stirred at room temperature for 63 hours. Water and3N hydrochloric acid were added to the solution, and it was extractedwith ethyl acetate. The organic layer was washed in turn with water andsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by chromatography (silica gel,hexane:ethyl acetate=6:4) to give the title compound (2.93 g).

¹H-NMR (CDCl₃): 1.26-1.34 (m, 4H), 1.35-1.48 (m, 6H), 1.61 (t, 2H, J=6.8Hz), 1.69 (t, 2H, J=6.8 Hz), 1.74-1.79 (m, 1H), 3.54 (t, 2H, J=6.8 Hz),3.64-3.73 (m, 2H), 4.50 (s, 2H), 7.26-7.39 (m, 5H).

PREPARATION EXAMPLE 3D-2{2-[1-(2-Iodoethyl)cyclohexyl]ethoxymethyl]benzene

Using 2-[1-(2-benzyloxyethyl)cyclohexyl]ethanol (1.63 g), the titlecompound (1.87 g) was obtained in the same manner as in PreparationExample 3A-3.

¹H-NMR (CDCl₃) δ: 1.23-1.33 (m, 4H), 1.35-1.48 (m, 6H), 1.62 (t, 2H,J=7.2 Hz), 1.93-2.02 (m, 2H), 3.12-3.20 (m, 2H), 3.49 (t, 2H, J=7.2 Hz),4.49 (s, 2H), 7.22-7.40 (m, 5H).

PREPARATION EXAMPLE 3D-3 Dimethyl2-{2-[1-(2-benzyloxyethyl)cyclohexyl]ethyl}malonate

To a suspension of 60% sodium hydride/mineral oil (613 mg) inN,N-dimethylformamide (15 mL) was added malonate (1.84 mL) at roomtemperature. After stirring the solution at room temperature for 15minutes, a solution of{2-[1-(2-iodoethyl)cyclohexyl]ethoxymethyl}benzene (1.5 g) inN,N-dimethylformamide (15 mL) was added thereto. The solution wasstirred at 60° C. for 60 hours. Water and 3N hydrochloric acid wereadded to the solution, and it was extracted with ethyl acetate. Theorganic layer was washed in turn with water and saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby chromatography (silica gel, hexane:ethyl acetate=85:15) to give thetitle compound (1.03 g). This product was subjected to the subsequentstep without further purification.

PREPARATION EXAMPLE 3D-42-{2-[1-(2-Benzyloxyethyl)cyclohexyl]ethyl}propane-1,3-diol

To a solution of dimethyl2-{2-[1-(2-benzyloxyethyl)cyclohexyl]ethyl}malonate (1.03 g) in diethylether (40 mL) was added lithium aluminum hydride (207 mg) under icecooling. After stirring the solution under ice cooling for 2 hours,water (0.2 mL) and a 15% aqueous sodium hydroxide solution (0.2 mL) weresuccessively added to the solution. The solution was stirred at roomtemperature for 15 minutes, water (0.6 mL) was added thereto, and it wasstirred for additional 30 minutes. The solution was dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by chromatography (silica gel,hexane:ethyl acetate=2:3) to give the title compound (320 mg).

¹H-NMR (CDCl₃) δ: 1.13-1,33 (m, 8H), 1.34-1.47 (m, 5H), 1.54-1.68 (m,4H), 2.23-2.37 (m, 2H), 3.47 (t, 2H, J=6.8 Hz), 3.57-3.67 (m, 2H),3.71-3.79 (m, 2H), 4.48 (s, 2H), 7.24-7.39 (m, 5H).

PREPARATION EXAMPLE 3D-52-[1-(4-Methoxymethoxy-3-methoxymethoxymethylbutyl)cyclohex-yl]ethanol

To a solution of2-{2-[1-(2-Benzyloxyethyl)cyclohexyl]ethyl}propane-1,3-diol (320 mg) indichloromethane (10 mL) were added diisopropylethylamine (0.69 mL) andchloromethylmethyl ether (0.23 mL) at room temperature. The solution wasstirred at room temperature for 3 hours. Chloroform was added to thesolution, and it was washed in turn with 1N hydrochloric acid, saturatedaqueous sodium bicarbonate solution and saturated aqueous sodiumchloride solution. The solution was dried over anhydrous magnesiumsulfate, and then, concentrated under reduced pressure. To a solution ofthe resulting residue in ethanol (30 mL) was added 10% palladium-carbon(50 mg). The solution was stirred at room temperature under hydrogenatmosphere for 16 hours. The catalyst was filtered off, and the filtratewas concentrated under reduced pressure. The resulting residue waspurified by chromatography (silica gel, hexane:ethyl acetate=3:2) togive the title compound (300 mg).

¹H-NMR (CDCl₃) δ: 1.20-1.48 (m, 14H), 1.53-1.65 (m, 2H), 1.73-1.82 (m,1H), 3.37 (s, 6H), 3.49-3.58 (m, 4H), 3.65 (t, 2H, J=7.6 Hz), 4.62 (s,4H).

PREPARATION EXAMPLE 3D-61-[4-Methoxymethoxy-3-(methoxymethoxymethyl)butyl]cyclohexylacetaldehyde

Using 2-[1-(4-methoxymethoxy-3-methoxymethoxybutyl)cyclohexyl]ethanol(300 mg), the title compound was obtained in the same manner as inPreparation Example 1A-3. This product was subjected to the subsequentstep without further purification.

PREPARATION EXAMPLE 3E-1 Dimethyl 1,1-cyclohexanediacetate

Using 1,1-cyclohexanediacetic acid (4.0 g), the title compound (4.56 g)was obtained in the same manner as in Preparation Example 1B-4.

¹H-NMR (CDCl₃) δ: 1.37-1.55 (m, 10H), 2.54 (s, 4H), 3.65 (s, 6H).

PREPARATION EXAMPLE 3E-2 Dimethyl2-(1-methoxycarbonylmethylcyclohexyl)malonate

To a solution of diisopropylamine (1.01 mL, 7.2 mmol) in tetrahydrofuran(8 mL) under cooling to −78° C. were added a solution of 1.5M n-butyllithium/hexane solution (4.4 mL). After stirring the solution at −78° C.for 1 hour, a solution of dimethyl 1,1-cyclohexanediacetate (685 mg) intetrahydrofuran (7 mL) was added thereto. The solution was stirred at−78° C. for 1 hour. Methyl chloroformate (0.93 mL) was then added to thesolution, and it was stirred at −78° C. for 1 hour. Water and 3Nhydrochloric acid were added to the solution, and it was extracted withethyl acetate. The organic layer was washed in turn with water andsaturated aqueous sodium chloride solution. The solution was dried overanhydrous magnesium sulfate, and then, concentrated under reducedpressure. The resulting residue was purified by chromatography (silicagel, hexane:ethyl acetate=85:15) to give the title compound (490 mg).

¹H-NMR (CDCl₃) δ: 1.23-1.68 (m, 8H), 1.71-1.81 (m, 2H), 2.81 (s, 2H),3.65 (s, 3H), 3.72 (s, 6H), 3.96 (s, 1H).

PREPARATION EXAMPLE 3E-32-[1-(2-Hydroxyethyl)cyclohexyl]propane-1,3-diol

To a solution of dimethyl 2-(1-methoxycarbonylmethylcyclohexyl)malonate(490 mg) in tetrahydrofuran (15 mL) was added lithium aluminum hydride(195 mg) under ice cooling. The solution was stirred under reflux for 1hour, and then, cooled on ice. Diethyl ether was added to the solution,followed by addition of water (0.2 mL) and a 15% aqueous sodiumhydroxide solution (0.2 mL). After stirring the solution at roomtemperature for 15 minutes, water (0.6 mL) was added thereto, and it wasstirred at room temperature for additional 30 minutes. The solution wasdried over anhydrous magnesium sulfate, and then, concentrated underreduced pressure. The resulting residue was purified by chromatography(silica gel, chloroform:methanol=85:15) to give the title compound (200mg).

¹H-NMR (CDCl₃) δ: 1.23-1.54 (m, 10H), 1.62-1.72 (m, 2H), 1.77-1.96 (m,1H), 3.69 (t, 2H, J=11.2 Hz), 3.75-3.83 (m, 2H), 3.96 (dd, 2H, J=4.0 Hz,11.2 Hz).

PREPARATION EXAMPLE 3E-42-[1-(2-Phenyl-1,3-dioxan-5-yl)cyclohexyl]ethanol

To a solution of 2-[1-(2-hydroxyethyl)cyclohexyl]propane-1,3-diol (200mg) in N,N-dimethylformamide (8 mL) were added benzaldehyde diethylacetal (752 mg) and p-toluenesulfonic acid pyridinium salt (48 mg) atroom temperature. After stirring the solution at room temperature for 16hours, saturated aqueous sodium bicarbonate solution was added thereto,and it was extracted with ethyl acetate. The organic layer was washed inturn with water and saturated aqueous sodium chloride solution (0.2 mL)and dried over anhydrous magnesium sulfate, and then, concentrated underreduced pressure. The resulting residue was purified by chromatography(silica gel, hexane:ethyl acetate=4:6) to give the title compound (100mg).

¹H-NMR (CDCl₃) δ: 1.22-1.97 (m, 12H), 2.24 (tt, 1H, J=4.0 Hz, 11.6 Hz),3.62-3.74 (m, 2H), 3.88 (t, 2H, J=11.2 Hz), 4.27 (dd, 1H, J=4.4 Hz, 11.2Hz), 5.38 (s, 1H), 7.29-7.40 (m, 3H), 7.42-7.51 (m, 2H).

PREPARATION EXAMPLE 3E-5[1-(2-Phenyl-1,3-dioxan-5-yl)cyclohexyl]acetaldehyde

Using 2-[1-(2-phenyl-1,3-dioxan-5-yl)cyclohexyl]ethanol (100 mg), thetitle compound was obtained in the same manner as in Preparation Example1A-3. This product was subjected to the subsequent step without furtherpurification.

PREPARATION EXAMPLE 3F-12-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)cyclohexyl]ethanol

To a solution of 2-[1-(2-hydroxyethyl)cyclohexyl]propane-1,3-diol (200mg) in acetone (10 mL) were added 2,2,-dimethoxypropane (206 mg) andp-toluenesulfonic acid (17 mg) at room temperature. After stirring thesolution at room temperature for 48 hours, a saturated aqueous sodiumbicarbonate solution was added thereto, and it was concentrated underreduced pressure. To the resulting residue were added diethyl ether andwater, and it was extracted with diethyl ether. The organic layer waswashed in turn with 0.5N hydrochloric acid, water and saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. The resulting residue waspurified by chromatography (silica gel, hexane:ethyl acetate=1:1 to 1:2)to give the title compound (190 mg).

¹H-NMR (CDCl₃) δ: 1.24-1.56 (m, 9H), 1.37 (s, 3H), 1.42 (s, 3H), 1.66(t, 2H, J=7.6 Hz), 2.00 ? 2.10 (m, 1H), 2.16 ? 2.26 (m, 1H), 3.68 (t,2H, J=7.6 Hz), 3.80 (dd, 2H, J=4.8 Hz, 7.2 Hz), 3.88 (t, 2H, J=7.2 Hz).

PREPARATION EXAMPLE 3F-22-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)cyclohexyl]acetaldehyde

Using 2-[1-(2,2-dimethyl-1,3-dioxan-5-yl)cyclohexyl]ethanol (190 mg),the title compound was obtained in the same manner as in PreparationExample 3A-6. This product was subjected to the subsequent step withoutfurther purification.

PREPARATION EXAMPLE 3G-1 Diethyl2-(2-{1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl}ethyl)-2-ethoxycarbonylsuccinate

Using tert-butyl-{2-[1-iodoethyl]cyclohexyl}ethoxy}diphenylsilane (1.77g) and triethyl 1,1,2-ethanetricarboxylate (2.51 g), the title compound(1.43 g) was obtained in the same manner as in Preparation Example 3B-1.This product was subjected to the subsequent step without furtherpurification.

PREPARATION EXAMPLE 3G-22-(2-{1-[2-(tert-Butyldiphenylsiloxy)ethyl]cyclohexyl}ethyl)-2-hydroxymethylbutane-1,4-diol

To a solution of diethyl2-(2-{1-[2-(tert-butyldipohenylsiloxy)ethyl]cyclohexyl}ethyl)-2-ethoxycarbonylsuccinate(1.0 g) in diethyl ether (20 mL) was added lithium aluminum hydride (178mg) under ice cooling. After stirring the solution under ice cooling for1.5 hours, water (0.18 mL) and a 15% aqueous sodium hydroxide solution(0.18 mL) were successively added thereto. The solution was stirred atroom temperature for 15 minutes. Water (0.54 mL) was then added to thesolution, and it was stirred at room temperature for additional 30minutes. The solution was dried over anhydrous magnesium sulfate andfiltered. Chloroform was added to the solid, and the solution wasstirred at room temperature for 2 hours, followed by filtration. Thecombined filtrate was concentrated under reduced pressure. The resultingresidue was purified by chromatography (silica gel, hexane:ethylacetate=1:4) to give the title compound (230 mg).

¹H-NMR (CDCl₃) δ: 1.01-1.44 (m, 10H), 1.04 (s, 9H), 1.52-1.62 (m, 4H),2.94-3.19 (m, 3H), 3.40-3.50 (m, 4H), 3.58-3.68 (m, 4H), 7.35-7.46 (m,6H), 7.64-7.73 (m, 4H).

PREPARATION EXAMPLE 3G-32-(Acetoxymethyl)-2-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane

To a solution of2-(2-{1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl}ethyl)-2-hydroxymethylbutan-1,4-diol(300 mg) in pyridine (5.0 mL) was added acetic anhydride (5.0 mL) atroom temperature. After stirring the solution at room temperature for 16hours, it was concentrated under reduced pressure to give the titlecompound (340 mg).

¹H-NMR (CDCl₃) δ: 0.97 (s, 9H), 1.03-1.39 (m, 12H), 1.51-1.65 (m, 6H),1.98 (s, 6H), 2.01 (s, 3H), 3.64 (t, 2H, J=7.6 Hz), 3.87 (s, 4H), 4.04(t, 2H, J=7.2 Hz), 7.35-7.46 (m, 6H), 7.64-7.71 (m, 4H).

PREPARATION EXAMPLE 3G-42-(Acetoxymethyl)-2-[2-[1-(2-hydroxyethyl)cyclohexyl]ethyl]-1,4-diacetoxybutane

To a solution of2-(acetoxymethyl)-2-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane(340 mg) in methanol (5 mL) and tetrahydrofuran (3 mL) was added 3Nhydrochloric acid (2.0 mL) at room temperature. After stirring thesolution at room temperature for 5.5 hours, water was added thereto. Thesolution was concentrated under reduced pressure to distill off methanoland tetrahydrofuran, and it was extracted with ethyl acetate. Theorganic layer was washed in turn with water and saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, and then,concentrated under reduced pressure. The resulting residue was purifiedby column chromatography (silica gel, hexane:ethyl acetate=4:6) to givethe title compound (110 mg).

¹H-NMR (CDCl₃) δ: 1.17-1.50 (m, 12H), 1.52-1.64 (m, 4H), 1.70 (t, 2H,J=7.2 Hz), 2.04 (s, 3H), 2.07 (s, 6H), 3.64 (t, 2H, J=8.0 Hz), 3.96 (s,4H), 4.14 (t, 2H, J=7.2 Hz).

PREPARATION EXAMPLE 3G-52-(Acetoxymethyl)-2-[2-[1-(formylmethyl)cyclohexyl]ethyl]-1,4-diacetoxybutane

Using2-(acetoxymethyl)-2-[2-[1-(2-hydroxyethyl)cyclohexyl]ethyl]-1,4-diacetoxybutane(110 mg), the title compound was obtained in the same manner as inPreparation Example 3A-6. This product was subjected to the subsequentstep without further purification.

PREPARATION EXAMPLE 3H-1 Dimethyl2-(2-{1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl}ethyl)-2-pent-4-enylmalonate

To a solution of dimethyl2-(2-{1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl}ethyl)malonate(1.30 g) in N,N-dimethylformamide (15 mL) were added 5-bromo-1-pentene(813 mg) and potassium tert-butoxide (334 mg) successively at roomtemperature. After stirring the solution at 60° C. for 2 hours, waterand 3N hydrochloric acid were added thereto, and it was extracted withethyl acetate. The organic layer was washed in turn with water,saturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate, andthen concentrated under reduced pressure. The resulting residue waspurified by chromatography (silica gel, hexane:ethyl acetate=92:8) togive the title compound (910 mg).

¹H-NMR (CDCl₃) δ: 1.03 (s, 9H), 1.10-1.44 (m, 13H), 1.54-1.64 (m, 3H),1.72-1.86 (m, 4H), 1.96-2.05 (m, 2H), 3.57-3.67 (m, 2H), 3.61 (s, 6H),4.90-5.02 (m, 2H), 5.64-5.78 (m, 1H), 7.31-7.47 (m, 6H), 7.62-7.74 (m,4H).

PREPARATION EXAMPLE 3H-22-(2-{1-[2-(tert-Butyldiphenylsiloxy)ethyl]cyclohexyl}ethyl)-2-pent-4-enylpropane-1,3-diol

To a solution of dimethyl2-(2-{1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl}ethyl)-2-pent-4-enylmalonate(910 mg) in diethyl ether (15 mL) was added lithium aluminum hydride(117 mg) under ice cooling. After stirring the solution at roomtemperature for 1 hour, water (0.12 mL) and a 15% aqueous sodiumhydroxide solution (0.12 mL) were successively added thereto. Thesolution was stirred at room temperature for 15 minutes. Water (0.36 mL)was then added and the solution was stirred at room temperature foradditional 15 minutes. The solution was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The resulting residuewas purified by chromatography (silica gel, hexane:ethyl acetate=6:4) togive the title compound (640 mg).

¹H-NMR (CDCl₃) δ: 0.97-1.42 (m, 16H), 1.03 (s, 9H), 1.53-1.64 (m, 3H),1.94-2.05 (m, 3H), 3.38-3.52 (m, 4H), 3.65 (t, 2H, J=8.0 Hz), 4.89-5.00(m, 2H), 5.66-5.80 (m, 1H), 7.33-7.49 (m, 6H), 7.63-7.77 (m, 4H).

PREPARATION EXAMPLE 3H-3{2-[1-[3,3-Bis(benzyloxymethyl)oct-7-enyl]cyclohexyl]ethoxy}-tert-butyldiphenylsilane

To a solution of2-(2-{1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl}ethyl)-2-pent-4-enylpropane-1,3-diol(640 mg) in dichloromethane (12 mL) were added pyridine (0.67 mL) andbenzoyl chloride (0.55 mL) at room temperature. After stirring thesolution at room temperature for 16 hours, it was concentrated underreduced pressure. The residue was extracted by addition of diethyl etherand 1N sodium hydroxide. The organic layer was washed in turn withwater, 1N hydrochloric acid, saturated aqueous sodium bicarbonatesolution and saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, and then, concentrated under reducedpressure. The resulting residue was purified by chromatography (silicagel, hexane:ethyl acetate=94:6) to give the title compound (840 mg).

¹H-NMR (CDCl₃) δ: 1.01 (s, 9H), 1.10-1.44 (m, 18H), 1.51-1.61 (m, 2H),1.93-2.03 (m, 2H), 3.64 (t, 2H, J=8.0 Hz), 4.18 (d, 2H, J=11.2 Hz), 4.23(d, 2H, J=11.2 Hz), 4.85-4.99 (m, 2H), 5.61-5.75 (m, 1H), 7.32-7.45 (m,10H), 7.49-7.57 (m, 2H), 7.60-7.69 (m, 4H), 7.95-8.03 (m, 4H).

PREPARATION EXAMPLE 3H-4

Methyl5,5-bis(benzyloxymethyl)-7-{1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl}heptanoate

To a solution of{2-[1-[3,3-bis(benzyloxymethyl)oct-7-enyl]cyclohexyl]ethoxy}-tert-butyldiphenylsilane(840 mg) in carbon tetrachloride (3 mL), acetonitrile (3 mL) and water(4.5 mL) were added sodium periodate (1.98 g) and ruthenium trichloridemonohydrate (10.3 g) at room temperature. After stirring the solution atroom temperature for 4 hours, water was added thereto and it wasextracted with chloroform. The organic layer was dried over anhydrousmagnesium sulfate, and then, concentrated under reduced pressure. To asolution of the resulting residue in methanol (1.5 mL)/benzene (7.5 mL)was added a 2M trimethylsilyldiazomethane/hexane solution (1.0 mL) underice cooling. After stirring the solution under ice cooling for 30minutes, it was concentrated under reduced pressure. The resultingresidue was purified by chromatography (silica gel, hexane:ethylacetate=85:15) to give the title compound (520 mg).

¹H-NMR (CDCl₃) δ: 1.00 (s, 9H), 1.09-1.37 (m, 14H), 1.38-1.47 (m, 2H),1.52-1.61. (m, 4H), 2.25 (t, 2H, J=6.8 Hz), 3.57 (s, 3H), 3.65 (t, 2H,J=8.0 Hz), 4.19 (d, 2H, J=11.2 Hz), 4.23 (d, 2H, J=11.2 Hz), 7.31-7.44(m, 10H), 7.49-7.57 (m, 2H), 7.60-7.66 (m, 4H), 7.95-8.02 (m, 4H).

PREPARATION EXAMPLE 3H-5 Methyl5,5-bis(benzyloxymethyl)-7-[1-(2-hydroxyethyl)cyclohexyl]-heptanoate

Using methyl5,5-bis(benzyloxymethyl)-7-{1-[2-(tert-butyldiphenylsiloxy)-ethyl]cyclohexyl}heptanoate(520 mg), the title compound (360 mg) was obtained in the same manner asin Preparation Example 3B-2.

¹H-NMR (CDCl₃) δ: 1.20-1.62 (m, 18H), 1.65-1.79 (m, 2H), 2.35 (t, 2H,J=6.8 Hz), 3.55-3.67 (m, 2H), 3.63 (s, 3H), 4.30 (s, 4H), 7.40-7.47 (m,4H), 7.53-7.60 (m, 2H), 7.98-8.05 (m, 4H).

PREPARATION EXAMPLE 3H-6 Methyl5,5-bis(benzyloxymethyl)-7-[1-(formylmethyl)cyclohexyl]heptanoate

Using methyl5,5-bis(benzyloxymethyl)-7-[1-(2-hydroxyethyl)cyclohexyl]-heptanoate(170 mg), the title compound was obtained in the same manner as inPreparation Example 3A-6. This product was subjected to the subsequentstep without further purification.

PREPARATION EXAMPLE 3I-13-[1-[2-(tert-Butyldiphenylsiloxy)ethyl]cyclohexyl]propioni-trile

To a solution of[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethanol (1.25 g)dissolved in benzene (15 mL) were added acetone cyanohydrin (0.40 mL),tri-n-butylphosphine (1.08 mL) and 1,1-azobis(N,N-dimethylformamide)(754 mg). The solution was stirred at room temperature for 18 hours. Thesolvent was distilled off under reduced pressure, ethyl acetate wasadded and insolubles were filtered off. The solvent was distilled offunder reduced pressure. The resulting residue was purified by columnchromatography (silica gel, hexane:ethyl acetate=5:1) to give the titlecompound (1.07 g).

¹H-NMR (CDCl₃) 6: F1.05 (s, 9H), 1.14-1.18 (m, 2H), 1.25-1.29 (m, 2H),1.29-1.37 (m, 6H), 1.50 (t, 2H, J=7.3 Hz), 1.60-1.64 (m, 2H), 2.03-2.07(m, 2H), 3.64 (t, 2H, J=7.3 Hz), 7.38-7.47 (m, 6H), 7.65-7.68 (m, 4H).

PREPARATION EXAMPLE 3I-2 3-[1-(2-Hydroxyethyl)cyclohexyl]propionitrile

Using methyl3-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]propionitrile (260mg), the title compound (80 mg) was obtained in the same manner as inPreparation Example 3B-2.

¹H-NMR (CDCl₃) δ: 1.26-1.45 (m, 10H), 1.55-1.59 (m, 3H), 1.72-1.72 (m,2H), 2.28-2.32 (m, 2H), 3.69 (t, 2H, J=7.3 Hz).

PREPARATION EXAMPLE 3I-3 3-[1-(2-Bromoethyl)cyclohexyl]propionitrile

Using methyl 3-[1-(2-hydroxyethyl)cyclohexyl]propionitrile (80 mg), thetitle compound (98 mg) was obtained in the same manner as in PreparationExample 2B-2. This product was subjected to the subsequent step withoutfurther purification.

PREPARATION EXAMPLE 3I-1N-[2-[1-[2-(tert-Butyldiphenylsiloxy)ethyl]cyclohexyl]ethyl-phthalimide

2-[1-[2-(tert-Butyldiphenyl siloxy)ethyl]cyclohexyl]ethanol (1.23 g),phthalimide (530 mg) and triphenylphosphine (1.10 g) were dissolved intetrahydrofuran (15 mL) and stirred for 20 minutes. Diethylazocarboxylate (0.57 mL) was then added to the solution, and it wasstirred at room temperature for 18 hours. The solvent was distilled offunder reduced pressure, and the resulting residue was purified bychromatography (silica gel, 15-20% ethyl acetate:hexane) to give thetitle compound (1.08 g).

¹H-NMR (CDCl₃) δ: 1.05 (s, 9H), 1.26-1.39 (m, 10H), 1.53 (t, 2H, J=7.3Hz), 1.67 (t, 2H, J=7.3 Hz), 3.55 (m, 2H), 3.81 (t, 2H, J=7.3 Hz),7.36-7.39 (m, 6H), 7.69-7.71 (m, 6H), 7.82-7.84 (m, 2H).

PREPARATION EXAMPLE 3J-22-{1-[2-(tert-Butyldiphenylsiloxy)ethyl]cyclohexyl}ethylamine

To a solution ofN-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]-phthalimide (1.52g) dissolved in ethanol (30 mL) was added hydrazine monohydrate. Thereaction solution was heated under reflux for 4 hours. To this was addeddiethyl ether and the insolbles were filtered off. The solvent was thendistilled off under reduced pressure. To this was added chloroform, andthe solution was made basic by addition of a 1N aqueous hydroxidesolution. The solution was then extracted with chloroform. The organiclayer was dried over anhydrous magnesium sulfate, filtered, and then,the solvent was distilled off under reduced pressure to give the titlecompound (1.20 g).

¹H-NMR (CDCl₃) δ: 1.04 (s, 9H), 1.19-1.45 (m, 14H), 1.57 (t, 2H, J=7.3Hz), 2.50 (t like, 2H), 3.68 (t, 2H, J=7.8 Hz), 7.37-7.45 (m, 6H),7.67-7.69 (m, 4H).

PREPARATION EXAMPLE 3I-3N-(2-[1-[2-(tert-Butyldiphenylsiloxy)ethyl]cyclohexyl]ethyl)methanesulfonamide

To a solution of2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethylamine (409 mg)dissolved in dichloromethane (10 mL) was added triethylamine (0.28 mL).Methanesulfonyl chloride (0.12 mL) was added to the solution under icecooling, and it was stirred at that temperature for 2 hours. Saturatedaqueous sodium bicarbonate solution was added to the solution, and itwas extracted with chloroform. The organic layer was dried overanhydrous magnesium sulfate, filtered, and then, the solvent wasdistilled off under reduced pressure. The resulting residue was purifiedby column chromatography (silica gel, hexane:ethyl acetate=6:1) to givethe title compound (327 mg).

¹H-NMR (CDCl₃) δ: 1.05 (s, 9H), 1.22-1.46 (m, 10H), 1.46-1.51 (m, 2H),1.53-1.61 (m, 2H), 2.83 (s, 3H), 2.97-3.02 (m, 2H), 3.68-3.72 (m, 2H),3.94 (m, 1H), 7.38-7.46 (m, 6H), 7.66-7.68 (m, 4H).

PREPARATION EXAMPLE 3J-4N-[2-[1-(2-Hydroxyethyl)cyclohexyl]ethyl]methanesulfonamide

UsingN-(2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethyl)methanesulfonamide(317 mg), the title compound (153 mg) was obtained in the same manner asin Preparation Example 3B-2.

¹H-NMR (CDCl₃) δ: 1.26-1.32 (m, 4H), 1.42-1.45 m, 2H), 1.58-1.63 (m,4H), 2.40 (brs, 1H), 2.96 (s, 3H), 3.12 (m, 2H), 3.69 (t, 2H, J=7.3 Hz),5.13 (brs, 1H).

PREPARATION EXAMPLE 3I-5N-[2-[1-(Formylmethyl)cyclohexyl]ethyl]methanesulfonamide

Using N-[2-[1-(2-hydroxyethyl)cyclohexyl]ethyl]methanesulfonamide (153mg), the title compound was obtained in the same manner as inPreparation Example 1A-3. This product was subjected to the subsequentstep without further purification.

PREPARATION EXAMPLE 3K-1N-[2-[1-(2-hydroxyethyl)cyclohexyl]ethylphthalimide

UsingN-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethylphthalimide(1.08 g), the title compound (340 mg) was obtained in the same manner asin Preparation Example 3B-2.

¹H-NMR (CDCl₃, 400 MHz) δ: 1.28-1.51 (m, 10H), 1.55 (t like, 1H),1.62-1.67 (m, 2H), 1.71 (t, 2H, J=7.8 Hz), 3.67-3.71 (m, 2H), 3.79-3.84(q like, 2H), 7.71 (d, 2H, J=8.3 Hz), 7.83 (d, 2H, J=8.3 Hz).

PREPARATION EXAMPLE 3K-2N-[2-[1-(Formylmethyl)cyclohexyl]ethyl]phthalimide

Using N-[2-[1-[2-(hydroxyethyl)cyclohexyl]ethylphthalimide (340 mg), thetitle compound was obtained in the same manner as in Preparation Example1A-3. This product was subjected to the subsequent step without furtherpurification.

PREPARATION EXAMPLE 4-1 2-(1-Benzylpiperidin-4-ylamino)-5-methylpyridine

To 2-bromo-4-methylpyridine (15.5 g) was added4-amino-1-benzylpiperidine (68.5 g). The resulting solution was stirredat 180° C. for 9 hours and then at 150° C. for 6 hours. Ethyl acetateand water were then added to the solution followed by addition ofsaturated aqueous sodium bicarbonate solution. After separating liquidlayers, the organic layer was washed with water and saturated aqueoussodium chloride solution, dried over anhydrous sodium sulfate, and then,concentrated under reduced pressure. The resulting residue was purifiedby chromatography [silica gel, ethyl acetate-methanol-aqueous ammonia(90:10:0.1)] to give the title compound (11.5 g).

¹H-NMR (CDCl₃) δ: 1.45-1.56 (m, 2H), 1.97-2.07 (m, 2H), 2.16 (s, 3H),2.13-2.23 (m, 2H), 2.78-2.89 (m, 2H), 3.52 (s, 2H), 3.48-3.62 (m, 1H),4.22 (brd, 1H, J=8.4 Hz), 6.29 (d, 1H, J=8.4 Hz), 7.20-7.33 (m, 6H),7.88-7.90 (m, 1H).

PREPARATION EXAMPLE 4-2 Ethyl4-(5-methylpyridin-2-yl)piperidine-1-carboxylate

2-Bromo-5-methylpyridine (8.56 g), 1,3-bis(diphenylphosphino)propane(4.10 g) and sodium tert-butoxide (6.69 g) were suspended in toluene(500 mL), to which was added ethyl 4-amino-1-piperidinecarboxylate(10.28 g). Tris(dibenzylideneacetone)dipalladium (3.19 g) was added tothe suspension, and it was stirred at 70° C. for 4 hours. Ethyl acetatewas added to the reaction solution, and then, it was washed withsaturated aqueous sodium chloride solution, and dried (MgSO₄). Thesolvent was distilled off under reduced pressure. The resulting residuewas purified by chromatography (silica gel, ethyl acetate), and thencrystallized (ethyl acetate/hexane) to give the title compound (10.13g).

¹H-NMR (DMSO-d₆) δ: 1.19 (t, 3H, J=6.8 Hz), 1.22-1.33 (m, 2H), 1.83-1.91(m, 2H), 2.08 (s, 3H), 2.90-3.02 (m, 2H), 3.79-3.94 (m, 3H), 4.03 (q,2H, J=6.8 Hz), 6.07 (d, 1H, J=7.8 Hz), 6.39 (d, 1H, J=8.0 Hz), 7.17 (dd,1H, J=2.4 Hz, 8.0 Hz), 7.77 (d, 1H, J=2.4 Hz).

PREPARATION EXAMPLE 4-3 2-(Piperidin-4-ylamino)-5-methylpyridine

Synthetic Method 1

To a solution of 2-(1-benzylpiperidin-4-ylamino)-5-methylpyridine (11.3g) in ethanol (250 mL) was added 20% palladium hydroxide (4 g). Afterstirring the solution at room temperature under hydrogen atmosphere for48 hours, 20% palladium hydroxide (2 g) was further added. The solutionwas then stirred at room temperature under hydrogen atmosphere foradditional 99 hours. The catalyst was filtered off. After concentrationunder reduced pressure, the resulting residue was purified bychromatography [NH silica gel, chloroform:methanol=10:1]. The resultingcrude product was crystallized from ethyl acetate/hexane to give thetitle compound (5.97 g).

Synthetic Method 2

To ethyl 4-(5-methylpyridin-2-yl)piperidin-1-carboxylate (10.13 g) wasadded a 30% hydrobromic acid/acetic acid solution. The solution washeated under reflux for 3 hours. The solvent was distilled off underreduced pressure, and the resulting solid was washed with ethyl acetateto give the hydrobromide of the title compound as a pale purple solid.To this was added saturated aqueous sodium bicarbonate solution, and thesolution was extracted with 25% ethanol/chloroform. After drying(MgSO₄), the solvent was distilled off under reduced pressure and thenrecrystallized (ethanol-chloroform-ethyl acetate) to give the titlecompound (3.62 g).

¹H-NMR (DMSO-d₆) δ: 1.53-1.66 (m, 2H), 2.00-2.08 (m, 2H), 2.09 (s, 3H),2.98-3.06 (m, 2H), 3.22-3.32 (m, 2H), 3.39-3.49 (m, 1H), 6.30 (d, 1H,J=7.3 Hz), 6.42 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H, J=2.4 Hz, 8.8 Hz), 7.78(d, 1H, J=2.4 Hz).

PREPARATION EXAMPLE 4-4 tert-Butyl4-(p-toluidino)piperidin-1-carboxylate

To a solution of tert-butyl 4-oxopiperidin-1-carboxylate (5.01 g) andp-toluidine (2.69 g) dissolved in tetrahydrofuran (50 mL) were addedsodium triacetoxyborohydride (7.99 g) and then acetic acid (3.0 mL). Thereaction solution was stirred for 2 days. The reaction solution waspoured into saturated aqueous sodium bicarbonate solution, and it wasextracted with ethyl acetate. The extract was washed in turn with waterand saturated aqueous sodium chloride solution, and dried (MgSO₄). Thesolvent was distilled off under reduced pressure, and the resultingresidue was purified by chromatography (silica gel, 20% ethylacetate/hexane) to give the title compound (6.49 g).

¹H-NMR (DMSO-d₆) δ; 1.16-1.28 (m, 2H), 1.40 (s, 9H), 1.80-1.90 (m, 2H),2.14 (s, 3H), 2.80-3.00 (m, 2H), 3.29-3.40 (m, 1H), 3.78-3.92 (m, 2H),5.07 (d, 1H, J=8.3 Hz), 6.49 (d, 1H, J=8.3 Hz, 6.86 (d, 1H, J=8.3 Hz).

PREPARATION EXAMPLE 4-5 4-(p-Toluidino)piperidine

To a solution of tert-butyl 4-(p-toluidino)piperidin-1-carboxylate(32.06 g) dissolved in dichloromethane (200 mL) was addedtrifluoroacetic acid (100 mL) at room temperature. The solution wasstirred for 1 day. The solvent was distilled off under reduced pressure,and the resulting residue was solidified with isopropyl ether and washedto give the trifluoroacetate of the title compound (42.12 g). This saltwas desalted by a conventional method to give the title compound (18.03g).

¹H-NMR (CDCL₃) δ: 1.27-1.41 (m, 2H), 2.05-2.12 (m, 2H), 2.23 (s, 3H),2.68-2.78 (m, 2H), 3.10-3.19 (m, 2H), 3.31-3.41 (m, 1H), 6.54 (d, 1H,J=8.3 Hz), 6.93 (d, 2H, J=8.3 Hz).

EXAMPLE 1A-12-[1-(Cyclohexylmethyl)piperidin-4-ylamino]-5-methylpyridine

A solution of 2-(piperidin-4-ylamino)-5-methylpyridine (191 mg),diisopropylamine (202 mg) and cyclohexylmethyl bromide (212 mg) inethanol (2 mL) was refluxed for 16 hours. To the reaction solution wasadded ethyl acetate, and insolubles were filtered off, and then,concentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (NH silica gel, hexane:ethyl acetate=4:1)to give the title compound (216 mg).

¹H-NMR (CDCl₃) δ: 0.80-0.93 (m, 2H), 1.08-1.28 (m, 3H), 1.40-1.54 (m,3H), 1.65-1.80 (m, 5H), 1.96-2.13 (m, 6H), 2.16 (s, 3H), 2.74-2.82 (m,2H), 3.48-3.60 (m, 1H), 4.23 (brd, 1H, J=8.5 Hz), 6.30 (d, 1H, J=8.8Hz), 7.23 (dd, 1H, J=2.0 Hz, 8.8 Hz), 7.89 (d, 1H, J=2.0 Hz).

EXAMPLE 1A-22-[1-(2-Cyclohexylethyl)piperidin-4-ylamino]-5-methylpyridine

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and (2-bromoethyl)cyclohexane in the same manneras in Example 1A-1.

¹H-NMR (CDCl₃) δ: 0.85-0.98 (m, 2H), 1.08-1.28 (m, 4H), 1.35-1.43 (m,2H), 1.45-1.56 (m, 2H), 1.60-1.79 (m, 4H), 2.00-2.17 (m, 4H), 2.16 (s,3H), 2.32-2.38 (m, 2H), 2.80-2.92 (m, 2H), 3.52-3.63 (m, 1H), 4.22 (brd,1H, J=8.5 Hz), 6.30 (d, 1H, J=8.8 Hz), 7.23 (dd, 1H, J=2.0 Hz, 8.8 Hz),7.89 (d, 1H, J=2.0 Hz).

EXAMPLE 1A-32-[1-(3-Cyclohexylpropyl)piperidin-4-ylamino]-5-methylpyridine

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and (3-bromopropyl)cyclohexane in the samemanner as in Example 1A-1.

¹H-NMR (CDCl₃) δ 0.81-0.93 (m, 2H), 1.10-1.28 (m, 6H), 1.44-1.56 (m,4H), 1.60-1.74 (m, 5H), 2.00-2.18 (m, 4H), 2.16 (s, 3H), 2.27-2.33 (m,2H), 2.81-2.90 (m, 2H), 3.52-3.63 (m, 1H), 4.22 (brd, 1H, J=8.3 Hz),6.30 (d, 1H, J=8.8 Hz), 7.23 (dd, 1H, J=2.5 Hz, 8.8 Hz), 7.89 (d, 1H,J=2.5 Hz).

EXAMPLE 1A-42-[1-(4-Cyclohexylbutyl)piperidin-4-ylamino]-5-methylpyridi-ne

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and (4-bromobutyl)cyclohexane in the same manneras in Example 1A-1.

¹H-NMR (CDCl₃) δ: 0.75-0.93 (m, 2H), 1.07-1.33 (m, 8H), 1.45-1.56 (m,4H), 1.59-1.74 (m, 6H), 1.98-2.19 (m, 3H), 2.16 (s, 3H), 2.28-2.35 (m,2H), 2.78-2.93 (m, 2H), 3.51-3.62 (m, 1H), 4.22 (brd, 1H, J=8.4 Hz),6.30 (d, 1H, J=8.8 Hz), 7.23 (dd, 1H, J=2.4 Hz, 8.8 Hz), 7.90 (d, 1H,J=2.4 Hz); MS (ESI) m/z: 330 (MH⁺).

EXAMPLE 1A-52-[1-[2-[2-(Cyclohexylacetamido)phenyl]ethyl]piperidin-4-yl-amino]-5-methylpyridine

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example2B-2 in the same manner as in Example 1A-1.

¹H-NMR (CDCl₃) δ: 0.96-1.40 (m, 5H), 1.49-2.03 (m, 8H), 2.05-2.15 (m,2H), 2.17 (s, 3H), 2.26-2.39 (m, 4H), 2.60-2.68 (m, 2H), 2.72-2.79 (m,2H), 2.86-2.96 (m, 1H), 3.61-3.75 (m, 1H), 4.20 (brd, 1H, J=6.8 Hz),6.31 (d, 1H, J=8.8 Hz), 6.99-7.06 (m, 1H), 7.07-7.13 (m, 1H), 7.18-7.28(m, 1H), 7.88-7.98 (m, 1H), 9.93 (brs, 1H).

EXAMPLE 1A-6 Methyl[1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethyl]cy-clohexyl]acetate

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example1B-4 in the same manner as in Example 1A-1.

¹H-NMR (CDCl₃) δ: 1.34-1.56 (m, 12H), 1.58-1.65 (m, 2H), 2.00-2.08 (m,2H), 2.16 (s, 3H), 2.10-2.22 (m, 2H), 2.30 (s, 2H), 2.34-2.40 (m, 2H),2.83-2.91 (m, 2H), 3.52-3.62 (m, 2H), 3.64 (s, 3H), 4.22 (brd, 1H, J=8.3Hz), 6.30 (d, 1H, J=8.3 Hz), 7.23 (dd, 1H, J=2.4 Hz, 8.3 Hz), 7.89 (d,1H, J=2.4 Hz).

EXAMPLE 1A-7 Methyl[1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethyl]cy-clopentyl]acetate

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example1C-3 in the same manner as in Example 1A-1.

¹H-NMR (CDCl₃) δ: 1.46-1.72 (m, 12H), 2.02-2.05 (m, 2H), 2.12-2.16 (m,5H), 2.30 (s, 2H), 2.36-2.43 (m, 2H), 2.85 (m, 2H), 3.59 (m, 1H), 3.65(s, 3H), 4.22 (d, 1H, J=8.8 Hz), 6.30 (d, 1H, J=8.8 Hz), 7.23 (dd, 1H,J=2.4 Hz, 8.3 Hz), 7.89 (d, 1H, J=2.4 Hz); MS (ESI) m/z: 360 (MH⁺).

EXAMPLE 1A-8 tert-Butyl[2-[3-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]propyl]-phenyl]carbamate

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example2E-2 in the same manner as in Example 1A-1.

¹H-NMR (CDCl₃) δ: 1.56 (s, 9H), 1.69-1.89 (m, 4H), 2.05-2.21 (m, 6H),2.17 (s, 3H), 2.63-2.70 (m, 2H), 2.71-2.85 (m, 2H), 3.55-3.69 (m, 1H),4.21-4.34 (m, 1H), 6.29 (d, 1H, J=8.0 Hz), 7.00-7.08 (m, 1H), 7.09-7.28(m, 3H), 7.59 (brd, 1H, J=8.0 Hz), 7.88-7.93 (m, 1H), 9.52 (brs, 1H).

EXAMPLE 1A-9 tert-Butyl[2-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethyl]-phenyl]carbamate

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example2F-2 in the same manner as in Example 1A-1.

¹H-NMR (CDCl₃): 1.56 (s, 9H), 1.66-1.79 (m, 2H), 2.05-2.14 (m, 2H), 2.17(s, 3H), 2.23-2.36 (m, 2H), 2.55-2.62 (m, 2H), 2.69-2.78 (m, 2H),2.84-2.97 (m, 2H), 3.55-3.68 (m, 1H), 4.22 (brd, 1H, J=7.6 Hz), 6.29 (d,1H, J=8.8 Hz), 6.90-6.98 (m, 1H), 7.02-7.08 (m, 1H), 7.14-7.28 (m, 2H),7.84 (brd, 1H, J=6.8 Hz), 7.91 (d, 1H, J=2.4 Hz), 10.36 (brs, 1H).

EXAMPLE 1B-1 1-(3-Cyclohexylpropyl)-4-(p-toluidino)piperidine

To a solution of 4-(p-toluidino)piperidine trifluoroacetate (0.7726 g)dissolved in N,N-dimethylformamide (10 mL) were added(3-bromopropyl)cyclohexane (0.57 g) and potassium carbonate (1.02 g).The reaction solution was heated with stirring at 80° C. for 5 hours.Dichloromethane was added to the reaction solution, and the insolubleswere filtered off, and then, the solvent was distilled off under reducedpressure. The resulting residue was purified by chromatography [silicagel, dichloromethane-methanol-aqueous ammonia (95:5:0.3)] to give thetitle compound as a while solid (0.4879 g).

mp 249-252° C.; ¹H-NMR (DMSO-d₆): 0.79-0.92 (m, 2H), 1.09-1.26 (m, 6H),1.27-1.46 (m, 4H), 1.56-1.72 (m, 5H), 1.80-1.90 (m, 2H), 1.93-2.03 (m,2H), 2.13 (s, 3H), 2.19-2.27 (m, 2H), 2.73-2.82 (m, 2H), 3.06-3.15 (m,1H), 4.97 (d, 1H, J=8.3 Hz), 6.46 (d, 2H, J=8.3 Hz), 6.85 (d, 2H, J=8.3Hz).

EXAMPLE 1B-2 Methyl[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]acetate

The title compound was synthesized from the compound obtained inPreparation Example 4-5 and the compound obtained in Preparation Example1B-4 in the same manner as in Example 1B-1.

¹H-NMR (DMSO-d₆) δ: 1.25-1.47 (m, 12H), 1.47-1.53 (m, 2H), 1.81-1.89 (m,2H), 1.95-2.03 (m, 2H), 2.13 (s, 3H), 2.24-2.30 (m, 2H), 2.29 (s, 2H),2.75-2.82 (m, 2H), 3.06-3.16 (m, 1H), 3.56 (s, 3H), 4.98 (d, 1H, J=8.3Hz), 6.46 (d, 1H, J=8.3 Hz), 6.85 (d, 1H, J=8.3 Hz).

EXAMPLE 1B-32-[1-[2-[1-(2-Cyanoethyl)cyclohexyl]ethyl]piperidin-4-yl-amino]-5-methylpyridine

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example3I-3 in the same manner as in Example 1B-1.

¹H-NMR (CDCl₃) δ: 1.23-1.32 (m, 4H), 1.34-1.57 (m, 10H), 1.68-1.72 (m,2H), 2.07 (d, 2H, J=13.2 Hz), 2.16-2.18 (m, 5H), 2.24-2.31 (m, 4H),2.90-2.96 (m, 2H), 3.63 (m, 1H), 4.25 (d, 2H, J=7.8 Hz), 6.31 (d, 1H,J=8.3 Hz), 7.23 (dd, 1H, J=2.4, 8.3 Hz), 7.89 (d, 1H, J=2.4 Hz).

EXAMPLE 1B-41-[2-[1-(2-Cyanoethyl)cyclohexyl]ethyl]-4-(p-toluidino)pipe-ridine

The title compound was synthesized from the compound obtained inPreparation Example 4-5 and the compound obtained in Preparation Example3I-3 in the same manner as in Example 1B-1.

¹H-NMR (DMSO-d₆) δ: 1.29-1.45 (m, 14H), 1.56-1.63 (m, 2H), 1.82-1.90 (m,2H), 1.96-2.04 (m, 2H), 2.13 (s, 3H), 2.17-2.24 (m, 2H), 2.33-2.40 (m,2H), 2.78-2.85 (m, 2H), 3.06-3.17 (m, 1H), 4.99 (d, 1H, J=7.3 Hz), 6.47(d, 2H, J=8.3 Hz), 6.85 (d, 2H, J=8.3 Hz).

EXAMPLE 1B-5 tert-Butyl[2-[3-[4-(p-toluidino)piperidine-1-yl]propyl]phenyl]carbamate

The title compound was synthesized from the compound obtained inPreparation Example 4-5 and the compound obtained in Preparation Example2E-2 in the same manner as in Example 1B-1.

¹H-NMR (CDCl₃) δ: 1.60 (s, 9H), 1.63-1.78 (m, 2H), 1.78-1.89 (m, 2H),1.99-2.16 (m, 6H), 2.24 (s, 3H), 2.59-2.70 (m, 2H), 2.72-2.87 (m, 2H),3.22-3.39 (m, 1H), 6.44-6.54 (m, 2H), 6.91-7.22 (m, 5H), 7.51-7.64 (m,1H), 9.46-9.57 (m, 1H).

EXAMPLE 1C-13-[1-[4-(5-Methylpyridin-2-ylamino)piperidin-1-yl]methylcyclohexyl]propylacetate

To a solution of acetic acid (1-hydroxymethylcyclohexyl)propyl ester(310 mg) in dichloromethane (15 mL) were added pyridine (0.18 mL) andanhydrous trifluoromethanesulfonic acid (0.37 mL) under ice cooling.After stirring the solution under ice cooling for 10 minutes, water andchloroform were added thereto and the liquid layers were separated. Theorganic layer was washed in turn with 1N hydrochloric acid, saturatedaqueous sodium bicarbonate solution and saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, and then,concentrated under reduced pressure. To the residue was added2-(piperidin-4-ylamino)-5-methylpyridine (416 mg) and the solution wasstirred at 60° C. for 1.5 hours. After allowing the mixture to cool toroom temperature, it was purified by chromatography (NH silica gel,hexane:ethyl acetate=4:1) to give the title compound (190 mg).

¹H-NMR (CDCl₃) δ: 1.21-1.68 (m, 16H), 1.89-1.99 (m, 2H), 2.04 (s, 3H),2.13 (s, 2H), 2.16 (s, 3H), 2.32-2.41 (m, 2H), 2.68-2.76 (m, 2H),3.44-3.55 (m, 1H), 4.03 (t, 2H, J=6.8 Hz), 4.23 (brd, 1H, J=8.0 Hz),6.29 (d, 1H, J=8.4 Hz), 7.23 (dd, 1H, J=2.4 Hz, 8.4 Hz), 7.89 (d, 1H,J=2.4 Hz); MS (ESI) m/z: 388 (MH⁺).

EXAMPLE 1D-1 Methyl1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethyl]cyclohexanecarboxylate

To a solution of 2-(piperidin-4-ylamino)-5-methylpyridine (191 mg) andmethyl 1-(2-oxoethyl)cyclohexanecarboxylate (250 mg) in tetrahydrofuran(10 mL) were added acetic acid (150 mg) and sodium triacetoxyborohydride (424 mg) at room temperature. The solution was stirred atroom temperature for 20 hours. Saturated aqueous sodium bicarbonatesolution was added to the solution, and it was extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate, andthen, concentrated under reduced pressure. The resulting residue waspurified by chromatography [silica gel, ethyl acetate-methanol-aqueousammonia (90:10:0.1)] to give the title compound (30 mg).

¹H-NMR (CDCl₃) δ: 1.11-1.63 (m, 10H), 1.67-1.79 (m, 2H), 1.96-2.21 (m,6H), 2.16 (s, 3H), 2.22-2.33 (m, 2H), 2.78-2.92 (m, 2H), 3.50-3.62 (m,1H), 3.67 (s, 3H), 4.26 (brd, 1H, J=8.8 Hz), 6.26-6.33 (m, 1H),7.20-7.25 (m, 1H), 7.86-7.91 (m, 1H).

EXAMPLE 1D-22-[1-[3-[2-(Cyclohexylacetamido)phenyl]propyl]piperidin-4-ylamino]-5-methypyridine

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example2A-4 in the same manner as in Example 1D-1. This product was subjectedto the subsequent step without further purification.

EXAMPLE 1D-32-[1-(2-Cyclooctylethyl)piperidin-4-ylamino]-5-methypyridine

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example1A-3 in the same manner as in Example 1D-1.

¹H-NMR (CDCl₃) δ: 1.19-1.73 (m, 19H), 2.00-2.12 (m, 2H), 2.13-2.27 (m,2H), 2.16 (s, 3H), 2.87-2.99 (m, 2H), 3.54-3.68 (m, 1H), 4.25-4.53 (m,1H), 6.31 (d, 1H, J=8.4 Hz), 7.23 (dd, 1H, J=2.4 Hz, 8.4 Hz), 7.85-7.91(m, 1H).

EXAMPLE 1D-4 Methyl4-[1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethyl]-cyclohexyl]butyrate

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example1F-3 in the same manner as in Example 1D-1

¹H-NMR (CDCl₃) δ: 1.18-1.65 (m, 16H), 2.00-2.38 (m, 10H), 2.16 (s, 3H),2.86-2.98 (m, 2H), 3.56-3.70 (m, 1H), 3.68 (s, 3H), 4.25 (brd, 1H, J=8.8Hz), 6.30 (d, 1H, J=8.4 Hz), 7.23 (dd, 1H, J=2.4 Hz, 8.4 Hz), 7.89 (d,1H, J=2.4 Hz); MS (ESI) m/z: 402 (MH⁺).

EXAMPLE 1D-5 Triethyl3-[1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethyl]-cyclohexyl]-1,1,1-propanetricarboxylate

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example3A-6 in the same manner as in Example 1D-1.

¹H-NMR (CDCl₃) δ: 1.23-1.61 (m, 25H), 2.00-2.10 (m, 4H), 2.12-2.26 (m,2H), 2.16 (s, 3H), 2.28-2.41 (m, 2H), 2.84-3.00 (m, 2H), 2.54-3.67 (m,1H), 4.23-4.30 (m, 1H), 6.31 (d, 1H, J=8.4 Hz), 7.23 (dd, 1H, J=2.4 Hz,8.4 Hz), 7.86-7.92 (m, 1H); MS (ESI) m/z: 560 (MH⁺).

EXAMPLE 1D-6 Dimethyl3-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]-1,1-propanedicarboxylate

The title compound was synthesized from the compound obtained inPreparation Example 4-5 and the compound obtained in Preparation Example3B-3 in the same manner as in Example 1D-1.

¹H-NMR (CDCl₃) δ: 1.18-1.55 (m, 16H), 1.78-1.88 (m, 2H), 2.01-2.19 (m,3H), 2.21 (s, 3H), 2.22-2.36 (m, 2H), 2.85-2.98 (m, 2H), 3.22-3.34 (m,2H), 3.75 (s, 6H), 6.53 (d, 2H, J=8.0 Hz), 6.98 (d, 2H, J=8.0 Hz); MS(ESI) m/z: 459 (MH⁺).

EXAMPLE 1D-72-[2-[1-[2-[4-(5-Methylpyridin-2-ylamino)piperidin-1-yl]eth-yl]cyclohexyl]ethyl]-1,3-diacetoxypropane

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example3C-3 in the same manner as in Example 1D-1. This product was subjectedto the subsequent step without further purification.

EXAMPLE 1D-82-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]-ethyl]-1,3-diacetoxypropane

The title compound was synthesized from the compound obtained inPreparation Example 4-5 and the compound obtained in Preparation Example3C-3 in the same manner as in Example 1D-1.

¹H-NMR (CDCl₃) δ: 1.19-1.64 (m, 19H), 1.87-1.96 (m, 1H), 2.01-2.23 (m,4H), 2.06 (s, 6H), 2.13 (s, 3H), 2.91-3.06 (m, 2H), 3.24-3.36 (m, 1H),4.00-4.14 (m, 4H), 6.53 (d, 2H, J=8.4 Hz), 6.98 (d, 2H, J=8.4 Hz); MS(ESI) m/z: 487 (MH⁺).

EXAMPLE 1D-92-[1-[2-[1-(4-Methoxymethoxy)-3-(methoxymethoxymethyl)butyl]cyclohexyl]ethyl]piperidin-4-ylamino]-5-methylpyridine

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example3D-6 in the same manner as in Example 1D-1.

¹H-NMR (CDCl₃) δ: 1.20-1.98 (m, 19H), 2.00-2.11 (m, 2H), 2.12-2.23 (m,2H), 2.16 (s, 3H), 2.26-2.37 (m, 2H), 2.83-2.97 (m, 2H), 3.37 (s, 6H),3.48-3.66 (m, 5H), 4.22-4.30 (m, 1H), 4.62 (s, 4H), 6.31 (d, 1H, J=8.4Hz), 7.23 (dd, 1H, J=2.4 Hz, 8.4 Hz), 7.86-7.92 (m, 1H); MS (ESI) m/z:492 (MH⁺).

EXAMPLE 1D-102-[1-[2-[1-(2-Phenyl-1,3-dioxan-5-yl)cyclohexyl]ethyl]piperidin-4-ylamino]-5-methylpyridine

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example3E-5 in the same manner as in Example 1D-1.

¹H-NMR (CDCl₃) δ: 1.29-1.43 (m, 5H), 1.44-1.67 (m, 9H), 2.02-2.13 (m,2H), 2.14-2.28 (m, 3H), 2.16 (s, 3H), 2.35-2.44 (m, 2H), 2.89-2.99 (m,2H), 3.56-3.69 (m, 1H), 3.90 (t, 2H, J=11.2 Hz), 4.23-4.37 (m, 3H), 5.39(s, 1H), 6.31 (d, 1H, J=8.4 Hz), 7.24 (dd, 1H, J=2.4 Hz, 8.4 Hz),7.30-7.39 (m, 3H), 7.44-7.51 (m, 2H), 7.87-7.91 (m, 1H).

EXAMPLE 1D-111-[2-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)cyclohexyl]ethyl]-4-(p-toluidino)piperidine

The title compound was synthesized from the compound obtained inPreparation Example 4-5 and the compound obtained in Preparation Example3F-2 in the same manner as in Example 1D-1.

¹H-NMR (CDCl₃) δ: 1.22-1.62 (m, 14H), 1.38 (s, 3H), 1.42 (s, 3H),1.95-2.20 (m, 5H), 2.23 (s, 3H), 2.29-2.41 (m, 2H), 2.84-2.97 (m, 2H),3.22-3.33 (m, 1H), 3.79 (dd, 2H, J=5.2 Hz, 11.6 Hz), 3.88 (t, 2H, J=11.6Hz), 6.52 (d, 2H, J=8.0 Hz), 6.98 (d, 2H, J=8.0 Hz); MS (ESI) m/z: 415(MH⁺).

EXAMPLE 1D-122-(Acetoxymethyl)-2-[2-[1-[2-[4-(5-methylpyridin-2-ylamino)-piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example3G-5 in the same manner as in Example 1D-1.

¹H-NMR (CDCl₃) δ: 1.15-1.58 (m, 16H), 1.65-1.75 (m, 4H), 1.99-2.19 (m,4H), 2.04 (s, 6H), 2.07 (s, 3H), 2.16 (s, 3H), 2.21-2.28 (m, 4H),2.81-2.92 (m, 2H), 3.53-3.65 (m, 1H), 3.96 (s, 4H), 4.14 (t, 2H, J=7.2Hz), 4.21-4.29 (m, 1H), 6.31 (d, 1H, J=8.0 Hz), 7.23 (dd, 1H, J=2.4 Hz,8.0 Hz), 7.89 (d, 1H, J=2.4 Hz).

EXAMPLE 1D-13 Methyl5,5-bis(benzoyloxymethyl)-7-[1-[2-[4-(5-methylpyridin-2-yl-amino)piperidin-1-yl]ethyl]cyclohexyl]heptanoate

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example3H-6 in the same manner as in Example 1D-1.

¹H-NMR (CDCl₃) δ: 1.14-1.58 (m, 20H), 1.65-1.78 (m, 2H), 1.86-2.03 (m,4H), 2.13-2.28 (m, 2H), 2.17 (s, 3H), 2.36 (t, 2H, J=6.8 Hz), 2.69-2.85(m, 2H), 3.40-3.55 (m, 1H), 3.63 (s, 3H), 4.20-4.38 (m, 1H), 4.29 (d,2H, J=11.2 Hz), 4.33 (d, 2H, J=11.2 Hz), 6.28 (d, 1H, J=8.8 Hz), 7.24(dd, 1H, J=2.4 Hz, 8.8 Hz), 7.39-7.47 (m, 4H), 7.52-7.59 (m, 2H),7.87-7.92 (m, 1H), 7.99-8.05 (m, 4H).

EXAMPLE 1D-14 Methyl5,5-bis(benzoyloxymethyl)-7-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]heptanoate

The title compound was synthesized from the compound obtained inPreparation Example 4-5 and the compound obtained in Preparation Example3H-6 in the same manner as in Example 1D-1.

¹H-NMR (CDCl₃) δ: 1.19-1.57 (m, 20H), 1.67-1.78 (m, 2H), 1.79-1.97 (m,4H), 2.12-2.22 (m, 2H), 2.24 (s, 3H), 2.35 (t, 2H, J=7.2 Hz), 2.67-2.79(m, 2H), 3.04-3.15 (m, 1H), 3.62 (s, 3H), 4.28 (d, 2H, J=11.6 Hz), 4.33(d, 2H, J=11.6 Hz), 6.50 (d, 2H, J=8.0 Hz), 6.98 (d, 2H, J=8.0 Hz),7.39-7.47 (m, 4H), 7.51-7.60 (m, 2H), 7.99-8.07 (m, 4H).

EXAMPLE 1D-15N-[2-[1-[2-[4-(5-Methylpyridin-2-ylamino)piperidin-1-yl]ethyl]cyclohexyl]ethyl]methanesulfonamide

The title compound was synthesized from the compound obtained inPreparation Example 4-3 and the compound obtained in Preparation Example3]-5 in the same manner as in Example 1D-1.

¹H-NMR (CDCl₃) δ: 1.25-1.28 (m, 5H), 1.42-1.50 (m, 8H), 1.56-1.61 (m,4H), 2.04 (d, 2H, J=10.7 Hz), 2.15-2.18 (m, 2H), 2.15 (s, 3H), 2.29 (t,2H, J=7.3 Hz), 2.92 (m, 2H), 2.95 (s, 3H), 3.10 (t, 2H, J=7.3 Hz), 3.61(m, 1H), 4.38 (d, 1H, J=8.8 Hz), 6.31 (d, 1H, J=8.8 Hz), 7.22 (dd, 1H,J=2.5, 8.3 Hz), 7.87 (s, 1H)

EXAMPLE 1E-1 2-(1-Cyclohexypiperidin-4-ylamino)-5-methylpyridine

To a solution of 2-(piperidin-4-ylamino)-5-methylpyridine (192 mg) andcyclohexanone (196 mg) in tetrahydrofuran (10 mL) was added sodiumtriacetoxyborohydride (636 mg). The reaction solution was stirred atroom temperature for 16 hours. Saturated aqueous sodium bicarbonatesolution was added to the solution, and it was extracted withchloroform. The extract was dried over anhydrous sodium sulfate, andthen, concentrated under reduced pressure. The resulting residue waspurified by chromatography (NH silica gel, hexane:ethyl acetate=2:1) togive the title compound (170 mg).

¹H-NMR (CDCl₃) δ: 1.03-1.34 (m, 5H), 1.52-1.69 (m, 3H), 1.76-1.98 (m,4H), 2.01-2.14 (m, 2H), 2.16 (s, 3H), 2.35-2.54 (m, 3H), 2.86-3.02 (m,2H), 3.55-3.69 (m, 1H), 4.23 (d, 1H, J=8.4 Hz), 6.30 (d, 1H, J=8.0 Hz),7.23 (dd, 1H, J=2.0 Hz, 8.0 Hz), 7.89 (d, 1H, J=2.0 Hz).

EXAMPLE 1F-12-[1-[2-[4-(5-Methylpyridin-2-ylamino)piperidin-1-yl]ethyl]-cyclohexyl]ethanol

To a solution of 2-(piperidin-4-ylamino)-5-methylpyridine (191 mg) and3-oxaspiro[5.5]undeca-2-ol (255 mg) in tetrahydrofuran (10 mL) was addedsodium triacetoxyborohydride (636 mg) at room temperature. Afterstirring the solution at room temperature for 87 hours, saturatedaqueous sodium bicarbonate solution was added thereto and it wasextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate, and then, concentrated under reduced pressure. Theresulting residue was purified by chromatography [silica gel, ethylacetate-methanol-aqueous ammonia(80:20:0.1)] to give the title compound(290 mg).

¹H-NMR (CDCl₃): 1.20-1.48 (m, 10H), 1.50-1.72 (m, 6H), 1.99-2.11 (m,2H), 2.16 (s, 3H), 2.18-2.30 (m, 2H), 2.39 (t, 2H, J=6.4 Hz), 2.87-3.02(m, 2H), 3.61-3.75 (m, 1H), 3.69 (t, 2H, J=6.4 Hz), 4.20 (brd, 1H, J=8.8Hz), 6.28 (d, 1H, J=8.4 Hz), 7.22 (dd, 1H, J=2.4 Hz, 8.4 Hz), 7.89 (d,1H, J=2.4 Hz); MS (ESI) m/z 346 (MH⁺).

EXAMPLE 1G-1 tert-Butyl[2-[1-[2-[4-(5-methylpyridin-2-ylamino)piperidin-1-yl]ethyl]cyclohexyl]ethyl]carbamate

4-(5-Methylpyridin-2-yl)aminopiperidine (0.31 g) andN-[2-[1-(formylmethyl)]cyclohexyl]ethylphthalimide obtained inPreparation Example 3K-2 were dissolved in dichloromethane (10 mL). Tothis was added sodium triacetoxyborohydride (0.71 g). The solution wasstirred for 3 days. Saturated aqueous sodium bicarbonate solution (20mL) was added to the reaction solution, and it was extracted with 25%ethanol/chloroform (20 mL). The extract was dried (MgSO₄), and then, thesolvent was distilled off under reduced pressure. The resulting residuewas purified by chromatography [silica gel,dichloromethane-methanol-aqueous ammonia (90:10:0.5)] to give a yellowoily substance (0.63 g). This was dissolved in ethanol (15 mL), to whichhydrazine monohydrate (0.15 g) was added. The solution was heated underreflux for 2 hours. The solvent was distilled off from the reactionsolution under reduced pressure. Then, the residue was again suspendedin dichloromethane (20 mL), to which triethylamine (0.32 g) anddi-tert-butyl dicarbonate (0.52 g) were added. The solution was stirredat room temperature for 17 hours. The insolubles were filtered off andthe solvent was distilled off under reduced pressure. The resultingresidue purified by chromatography [silica gel,dichloromethane-methanol-aqueous ammonia (97:3:0.2 to 95:5:0.3)] to givethe title compound (0.42 g).

¹H-NMR (DMSO-d₆): 1.23-1.30 (m, 4H), 1.31-1.48 (m, 12H), 1.38 (s, 9H),1.83-1.92 (m, 2H), 2.00-2.16 (m, 2H), 2.08 (s, 3H), 2.24-2.36 (m, 2H),2.77-2.86 (m, 2H), 2.87-2.95 (m, 2H), 3.56-3.68 (m, 1H), 5.64-5.72 (m,1H), 6.20-6.40 (m, 1H), 6.37 (d, 1H, J=8.3 Hz), 7.15 (dd, 1H, J=2.4 Hz,8.3 Hz), 7.76 (d, 1H, J=2.4 Hz).

EXAMPLE 1G-2N-[2-[4-(5-Methylpyridin-2-ylamino)piperidin-1-ylmethyl]-phenyl]cyclohexylacetamide

To a solution of 2-(piperidin-4-ylamino)-5-methylpyridine (150 mg) and2-nitrobenzylbromide (339 mg) in ethanol (5 mL) was addeddiisopropylamine (159 mg) at room temperature. The solution was stirredunder reflux for 20 hours. Ethyl acetate was then added to the solutionand the insolubles were filtered off, and then, concentrated underreduced pressure. The resulting residue was purified by chromatography[silica gel, ethyl acetate:methanol:aqueous ammonia (90/10/0.1)]. Theresulting residue was dissolved in ethanol (10 mL), to which platinumoxide (10 mg) was added. The solution was stirred at room temperatureunder hydrogen atmosphere for 4 hours. The catalyst was then filteredoff and the solution was concentrated under reduced pressure. To asolution of the residue and cyclohexylacetic acid (52 mg) indichloromethane (5 mL) were added 1-hydroxybenzotriazole (49 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg)under ice cooling. The solution was stirred at room temperature for 87hours. Chloroform was then added to the solution, and it was washed inturn with water and saturated aqueous sodium bicarbonate solution, driedover anhydrous sodium sulfate, and then, concentrated under reducedpressure. The resulting residue was purified by chromatography (NHsilica gel, hexane:ethyl acetate=2:1) to give the title compound (90mg).

¹H-NMR (CDCl₃) δ: 0.94-1.08 (m, 2H), 1.10-1.36 (m, 3H), 1.40-1.54 (m,2H), 1.63-1.78 (m, 3H), 1.79-1.95 (m, 3H), 2.07-2.18 (m, 4H), 2.15 (s,3H), 2.18-2.32 (m, 3H), 2.79-2.91 (m, 2H), 3.58 (s, 2H), 3.63-3.74 (m,1H), 4.21 (brd, 1H, J=7.6 Hz), 6.32 (d, 1H, J=8.4 Hz), 6.94-7.02 (m,1H), 7.04-7.10 (m, 1H), 7.21-7.32 (m, 2H), 7.88-7.93 (m, 1H), 8.26 (d,1H, J=8.4 Hz), 10.15 (brs, 1H).

EXAMPLE 1G-3N-[2-[2-[4-(p-Toluidino)piperidin-1-yl]ethyl]phenyl]cyclohexylacetamide

To a solution of 4-(p-tolyl)aminopiperidine trifluoroacetate (2.21 g)and (2-bromoethyl)-2-nitrobenzene (3.01 g) dissolved inN,N-dimethylformamide (20 mL) was added potassium carbonate (2.92 g).The solution was stirred under heating at 80° C. for 2 hours.Dichloromethane was added to the reaction solution and the insolubleswere filtered off, and the solvent was distilled off under reducedpressure. The resulting residue was purified by chromatography [silicagel, dichloromethane-methanol-aqueous:ammonia (95:5:0.3)] to give ayellow oily substance (0.6906 g). This was dissolved in acetic acid (20mL), to which 10% palladium carbon (0.20 g) was added. The mixture wasvigorously stirred at room temperature under hydrogen atmosphere for 1hour. The catalyst was filtered off and the solvent was distilled offunder reduced pressure. The resulting residue was purified bychromatography [silica gel, dichloromethane-methanol-aqueous ammonia(90:10:0.5)] to give a brown oily substance (0.5041 g). This substance,cyclohexaneacetic acid (0.35 g), 4-dimethylaminopyridine (0.50 g) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.62 g)were dissolved in N,N-dimethylformamide (10 mL). The solution wasstirred at room temperature for 15 hours. After addition of ethylacetate, the solution was washed in turn with saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution,dried (MgSO₄) and the solvent was distilled off under reduced pressure.The resulting residue was purified by chromatography [silica gel,dichloromethane-methanol-aqueous ammonia (95:5:0.3)] to give the titlecompound (0.4453 g).

¹H-NMR (DMSO-d₆) δ: 0.94-1.08 (m, 2H), 1.09-1.31 (m, 3H), 1.32-1.42 (m,2H), 1.58-1.83 (m, 6H), 1.84-1.92 (m, 2H), 2.08-2.13 (m, 2H), 2.12 9s,3H], 2.19-2.22 (m, 2H), 2.43-2.49 (m, 2H), 2.69-2.76 (m, 2H), 2.82-2.90(m, 2H), 3.08-3.20 (m, 1H), 5.01 (d, 1H, J=8.3 Hz), 6.48 (d, 2H, J=8.3Hz), 6.86 (d, 2H, J=8.3 Hz), 7.02-7.24 (m, 3H), 7.32-7.40 (m, 1H), 9.39(s, 1H).

EXAMPLE 1G-43-Cyclohexyl-N-[2-[3-[4-(p-toluidino)piperidin-1-yl]propyl]-phenyl]propionamide

To a solution of 4-(p-tolyl)aminopiperidine trifluoroacetate (2.08 g)and (3-bromopropenyl)-2-nitrobenzene (3.01 g) dissolved inN,N-dimethylformamide (20 mL) was added potassium carbonate (2.75 g).The solution was stirred with heating at 80° C. for 2 hours.Dichloromethane was added to the reaction solution and the insolubleswere filtered off, and the solvent was distilled off under reducedpressure. The resulting residue was purified by chromatography [silicagel, dichloromethane-methanol-aqueous:ammonia (95:5:0.3)] to give ayellow oily substance (1.05 g). This was dissolved in acetic acid (25mL), to which 10% palladium carbon (0.50 g) was added. The mixture wasvigorously stirred at room temperature under hydrogen atmosphere for 1hour. The catalyst was filtered off and the solvent was distilled offunder reduced pressure. The resulting residue was purified bychromatography [silica gel, dichloromethane-methanol-aqueous ammonia(90:10:0.5)] to give a brown oily substance (0.5443 g). Part of thesubstance (0.3870 g), cyclohexaneacetic acid (0.28 g),4-dimethylaminopyridine (0.50 g) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g)were dissolved in N,N-dimethylformamide (5 mL). The solution was stirredat room temperature for 18 hours. After addition of ethyl acetate, thesolution was washed in turn with saturated aqueous sodium bicarbonatesolution and saturated aqueous sodium chloride solution, dried (MgSO₄),and the solvent was distilled off under reduced pressure. The resultingresidue was purified by chromatography [silica gel,dichloro-methane-methanol-aqueous ammonia (97:3:0.2)] to give the titlecompound (0.4190 g).

¹H-NMR (DMSO-d₆) δ: 0.82-0.97 (m, 2H), 1.08-1.30 (m, 4H), 1.30-1.42 (m,2H), 1.47-1.56 (m, 2H), 1.57-1.78 (m, 7H), 1.84-1.92 (m, 2H), 1.96-2.04,(m, 2H), 2.13 (s, 3H), 2.25 (t, 2H, J=7.3 Hz), 2.28-2.36 (m, 2H), 2.56(t, 2H, J=7.3 Hz), 2.74-2.82 (m, 2H), 3.08-3.19 (m, 1H), 4.98 (d, 1H,J=8.3 Hz), 6.47 (d, 2H, J=8.3 Hz), 6.85 (d, 2H, J=8.3 Hz), 7.08-7.18 (m,2H), 7.19-7.21 (m, 1H), 7.25-7.32 (m, 1H), 9.23 (s, 1H).

EXAMPLE 1H-1 Benzyl1-[2-[4-(5-methylpiridin-2-ylamino)piperidin-1-yl]ethyl]cyclohexanecarboxylate

To a solution of 2-(piperidin-4-ylamino)-5-methylpyridine (277 mg) andbenzyl 1-(2-oxoethyl)cyclohexanecarboxylate (360 mg) in tetrahydrofuran(15 mL) was added acetic acid (207 mg) and triacetoxyborohydride (731mg) at room temperature. After stirring the solution for 18 hours,saturated aqueous sodium bicarbonate solution was added thereto and itwas extracted with ethyl acetate. The extract was dried over anhydroussodium sulfate, and then, concentrated under reduced pressure. Theresulting residue was purified by chromatography (NH silica gel,hexane:ethyl acetate=2:1) to give the title compound (520 mg).

¹H-NMR (CDCl₃) δ: 1.18-1.65 (m, 8H), 1.68-1.91 (m, 4H), 1.93-2.05 (m,6H), 2.13-2.24 (m, 2H), 2.16 (s, 3H), 2.67-2.81 (m, 2H), 3.45-3.58 (m,1H), 4.19 (brd, 1H, J=8.4 Hz), 5.13 (s, 2H), 6.29 (d, 1H, J=8.4 Hz),7.23 (dd, 1H, J=2.4 Hz, 8.4 Hz), 7.28-7.41 (m, 5H), 7.89 (d, 1H, J=2.4Hz); MS (ESI) m/z: 436 (MH⁺).

EXAMPLE 1H-21-[2-[4-(5-Methylpiridin-2-ylamino)piperidin-1-yl]ethyl]cyclohexanecarboxylicacid

To a solution of benzyl1-[2-[4-(5-methylpiridin-2-yl-amino)piperidin-1-yl]ethyl]cy-clohexanecarboxylate(160 mg, 0.37 mmol) in ethanol (16 mL) was added 10% palladium carbon(80 mg) at room temperature. The mixture was stirred at room temperatureunder hydrogen atmosphere for 24 hours. Acetic acid was added to themixture, and it was filtered with Celite and concentrated under reducedpressure. Methanol and diethyl ether were added to the residue, and thesolution was stirred under ice cooling for 1 hour. The crystals wererecovered by filtration to give the title compound (100 mg).

¹H-NMR (DMSO-d₆) δ: 1.15-1.39 (m, 5H), 1.42-1.57 (m, 5H), 1.65-1.76 (m,2H), 1.85-2.00 (m, 4H), 2.08 (s, 3H), 2.31-2.58 (m, 4H), 2.95-3.08 (m,2H), 3.66-3.78 (m, 1H), 6.10 (brd, 1H, J=6.8 Hz), 6.38 (d, 1H, J=8.4Hz), 7.18 (dd, 1H, J=2.4 Hz, 8.4 Hz), 7.74-7.79 (m, 1H).

EXAMPLE 2-1N-[1-(Cyclohexylmethyl)piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

To a solution of2-[1-(cyclohexylmethyl)piperidin-4-ylamino]-5-methylpyridine (216 mg)prepared in Preparation Example 1A-1 and triethylamine (152 mg) indichloromethane (3 mL) was added 2-furoyl chloride (0.11 mL) dropwiseunder ice cooling. The solution was stirred at room temperature for 18hours. Silica gel (NH silica gel) was added to the reaction solution,and it was concentrated under reduced pressure. The resulting residuewas purified by chromatography (NH silica gel, hexane:ethyl acetate=2:1)to give the title compound as a colorless crystal (271 mg).

Free Form

¹H-NMR (CDCl₃) δ: 0.74-0.87 (m, 2H), 1.05-1.28 (m, 3H), 1.35-1.47 (m,1H), 1.50-1.80 (m, 7H), 1.86-1.95 (m, 2H), 1.98-2.12 (m, 4H), 2.39 (s,3H), 2.84-2.92 (m, 2H), 4.70 (tt, 1H, J=4.0 Hz, 12.5 Hz), 5.92 (d, 1H,J=3.4 Hz), 6.18 (dd, 1H, J=1.4 Hz, 3.4 Hz), 6.99 (d, 1H, J=7.8 Hz),7.21-7.23 (m, 1H), 7.47-7.53 (m, 1H), 8.38-8.41 (m, 1H).

Hydrochloride

mp 220-230° C. (dec.); ¹H-NMR (CDCl₃): 0.97-1.30 (m, 5H), 1.62-1.70 (m,1H), 1.71-1.85 (m, 3H), 1.87-1.95 (m, 2H), 2.39-2.47 (m, 2H), 2.52-2.66(m, 2H), 2.59 (s, 3H), 2.78-2.83 (m, 2H), 3.02-3.16 (m, 2H), 3.50-3.57(m, 2H), 5.04-5.14 (m, 1H), 6.36 (dd, 1H, J=1.5 Hz, 3.4 Hz), 6.93 (d,1H, J=3.4 Hz), 7.12-7.13 (m, 1H), 7.69 (d, 1H, J=8.3 Hz), 8.28 (dd, 1H,J=1.5 Hz, 8.3 Hz), 8.49 (d, 1H, J=1.5 Hz), 11.55 (brs, 1H); MS (ESI)m/z: 382 (MH⁺); Anal. Calcd for C₂₃H₃₁N₃O₂.2HCl: C, 60.79; H, 7.32; N,9.25. Found: C, 60.66; H, 7.49; N, 9.08.

EXAMPLE 2-2N-[1-(2-Cyclohexylethyl)piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1A-2 in the same manner as in Example 2-1.

Free Form

¹H-NMR (CDCl₃) δ 0.82-0.95 (m, 2H), 1.05-1.27 (m, 4H), 1.28-1.36 (m,2H), 1.53-1.70 (m, 7H), 1.89-1.97 (m, 2H), 2.02-2.12 (m, 2H), 2.27-2.33(m, 2H), 2.38 (s, 3H), 2.92-2.98 (m, 2H), 4.74 (tt, 1H, J=4.0 Hz, 12.5Hz), 5.93 (d, 1H, J=3.4 Hz), 6.18 (dd, 1H, J=1.5 Hz, 3.4 Hz), 6.99 (d,1H, J=8.3 Hz), 7.22 (d, 1H, J=1.5 Hz), 7.50 (dd, 1H, J=2.0 Hz, 8.3 Hz),8.38 (d, 1H, J=2.0 Hz)

Hydrochloride

mp 130-140° C. (dec.); ¹H-NMR (CDCl₃) δ: 0.87-1.00 (m, 2H), 1.05-1.35(m, 4H), 1.60-1.75 (m, 7H), 2.34-2.50 (m, 4H), 2.59 (s, 3H), 2.92-3.06(m, 4H), 3.49-3.57 (m, 2H), 4.98-5.08 (m, 1H), 6.36 (dd, 1H, J=1.5 Hz,3.4 Hz), 6.94 (d, 1H, J=3.4 Hz), 7.11-7.13 (m, 1H), 7.61 (d, 1H, J=7.8Hz), 8.21 (dd, 1H, J=1.5 Hz, 7.8 Hz), 8.50 (dd, 1H, J=1.5 Hz), 12.06(brs, 1H); MS (ESI) m/z: 396 (MH⁺); Anal. Calcd forC₂₄H₃₃N₃O₂.2HCl.2/3H₂O: C, 59.99; H, 7.62; N, 8.75. Found: C, 59.99; H,7.78; N, 8.63.

EXAMPLE 2-3N-[1-(3-Cyclohexylpropyl)piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1A-3 in the same manner as in Example 2-1.

Free Form

mp 90-92° C.; ¹H-NMR (CDCl₃) δ: 0.77-0.90 (m, 2H), 1.08-1.24 (m, 6H),1.38-1.47 (m, 2H), 1.54-1.70 (m, 7H), 1.90-1.97 (m, 2H), 2.03-2.12 (m,2H), 2.22-2.28 (m, 2H), 2.38 (s, 3H), 2.92-2.98 (m, 2H), 4.74 (tt, 1H,J=4.0 Hz, 12.5 Hz), 5.93 (dd, 1H, J=0.5 Hz, 3.4 Hz), 6.19 (dd, 1H, J=1.5Hz, 3.4 Hz), 6.99 (d, 1H, J=7.8 Hz), 7.22 (dd, 1H, J=0.5 Hz, 1.5 Hz),7.50 (dd, 1H, J=2.4 Hz, 7.8 Hz), 8.38 (d, 1H, J=2.4 Hz); MS (ESI) m/z:410 (MH⁺); Anal. Calcd for C₂₅H₃₅N₃O₂: C, 73.31; H, 8.61; N, 10.26.Found: C, 73.32; H, 8.76; N, 10.34.

Hydrochloride

mp 193-199° C.; ¹H-NMR (CDCl₃) δ: 0.80-0.93 (m, 2H), 1.05-1.28 (m, 6H),1.60-1.73 (m, 5H), 1.79-1.90 (m, 2H), 2.25-2.45 (m, 4H), 2.50 (s, 3H),2.84-2.97 (m, 4H), 3.52-3.59 (m, 2H), 4.93-5.04 (m, 1H), 6.29 (dd, 1H,J=1.5 Hz, 3.4 Hz), 6.37-6.42 (m, 1H), 7.19-7.20 (m, 1H), 7.34 (d, 1H,J=8.3 Hz), 7.90 (d, 1H, J=8.3 Hz), 8.45 (s, 1H), 12.17 (brs, 1H); MS(ESI) m/z: 410 (MH⁺); Anal. Calcd for C₂₅H₃₅N₃O₂HCl 4/3H₂O: C, 63.88; H,8.29; N, 8.94. Found: C, 63.87; H, 8.02; N, 8.84.

EXAMPLE 2-4N-[1-(4-Cyclohexylbutyl)piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1A-4 in the same manner as in Example 2-1.

Free Form

¹H-NMR (CDCl₃): 0.75-0.85 (m, 2H), 1.04-1.29 (m, 8H), 1.35-1.45 (m, 2H),1.54-1.71 (m, 7H), 1.88-1.97 (m, 2H), 2.02-2.12 (m, 2H), 2.38 (s, 3H),2.90-2.99 (m, 2H), 4.74 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.92-5.95 (m, 1H),6.19 (dd, 1H, J=2.4 Hz, 3.6 Hz), 6.99 (d, 1H, J=8.0 Hz), 7.21-7.24 (m,1H), 7.50 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.38 (d, 1H, J=2.4 Hz).

Hydrochloride

mp 123-126° C.; ¹H-NMR (DMSO-d₆) δ 0.76-0.92 (m, 2H), 1.04-1.32 (m, 8H),1.53-1.71 (m, 7H), 1.81-2.06 (m, 4H), 2.37 (s, 3H), 2.86-3.14 (m, 4H),3.39-3.52 (m, 2H), 4.75 (tt, 1H, J=4.0 Hz, 11.6 Hz), 5.89 (d, 1H, J=7.6Hz), 6.35 (dd, 1H, J=1.6 Hz, 7.6 Hz), 7.24 (d, 1H, J=8.0 Hz), 7.54-7.59(m, 1H), 7.74 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.36-8.42 (m, 1H); MS (ESI)m/z: 424 (M⁺+1); IR (KBr) cm⁻¹: 3444, 2880, 1651, 1637, 1556, 1470,1322, 1189, 752; Anal. Calcd for C₂₆H₃₇N₃O₂—HCl 2H₂O: C, 62.95; H, 8.53;N, 8.47. Found: C, 63.21; H, 8.52; N, 8.28.

EXAMPLE 2-5N-[1-[2-[2-(Cyclohexylacetamido)phenyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1A-5 in the same manner as in Example 2-1.

Free Form

¹H-NMR (CDCl₃) δ: 0.82-0.97 (m, 2H), 1.06-1.34 (m, 4H), 1.59-1.88 (m,9H), 1.91-2.03 (m, 4H), 2.23-2.36 (m, 2H), 2.41 (s, 3H), 2.55-2.73 (m,4H), 2.91-3.01 (m, 2H), 4.74 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.98 (d, 1H,J=3.6 Hz), 6.21 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.95-7.10 (m, 3H), 7.16-7.24(m, 2H), 7.50-7.57 (m, 1H), 7.87 (d, 1H, J=8.0 Hz), 8.41 (d, 1H, J=2.4Hz), 9.86 (brs, 1H).

Hydrochloride

mp 117-120° C.; ¹H-NMR (DMSO-d₆) δ: 0.93-1.08 (m, 2H), 1.09-1.32 (m,3H), 1.58-1.98 (m, 8H), 2.00-2.13 (m, 2H), 2.20-2.32 (m, 2H), 2.38 (s,3H), 2.89-2.99 (m, 2H), 3.09-3.24 (m, 4H), 3.49-3.57 (m, 2H), 4.73-4.84(m, 1H), 5.89-5.94 (m, 1H), 6.36 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.14-7.34(m, 5H), 7.54-7.58 (m, 1H), 7.74 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.41 (d,1H, J=2.4 Hz), 9.37-9.42 (m, 1H), 9.72-9.87 (m, 1H); MS (ESI) m/z: 529(MH⁺); IR (KBr) cm⁻¹: 3435, 2923, 2850, 1646, 1522, 1469, 1449, 1341,1191.

EXAMPLE 2-6 Methyl[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetate

The title compound was synthesized from the compound obtained in Example1A-6 in the same manner as in Example 2-1.

Hydrochloride

mp 120-130° C. (dec); ¹H-NMR (CDCl₃) δ: 1.30-1.55 (m, 10H), 1.87-1.95(m, 2H), 2.26-(s, 2H), 2.30-2.50 (m, 4H), 2.58 (s, 3H), 2.94-3.10 (m,4H), 3.50-3.60 (m, 2H), 3.67 (s, 3H), 4.95-5.07 (m, 1H), 6.35 (dd, 1H,J=1.5 Hz, 3.5 Hz), 6.92 (d, 1H, J=3.5 Hz), 7.12 (d, 1H, J=1.5 Hz), 7.57(d, 1H, J=7.8 Hz), 8.18 (dd, 1H, J=1.5 Hz, 7.8 Hz), 8.51 (d, 1H, J=1.5Hz, 12.13 (brs, 1H).

EXAMPLE 2-7 Methyl[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclopentyl]acetate

The title compound was synthesized from the compound obtained in Example1A-7 in the same manner as in Example 2-1.

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.40-1.54 (m, 4H), 1.57-1.59 (m, 4H), 2.01-2.05 (d,2H, J=13.2 Hz), 2.28 (s, 2H), 2.36 (s, 3H), 2.99-3.04 (m, 4H), 3.48-3.55(m, 2H), 3.60 (s, 3H), 4.75 (m, 1H), 5.92 (d, 1H, J=3.4 Hz), 6.36 (dd,1H, J=2.0, 3.4 Hz), 7.24 (d, 1H, J=7.8 Hz), 7.57 (s, 1H), 7.74 (d, 1H,J=7.8 Hz), 8.40 (s, 1H); MS (ESI) m/z: 454 (MH⁺).

EXAMPLE 2-8 tert-Butyl[2-[3-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]propyl]phenyl]carbamate

The title compound was synthesized from the compound obtained in Example1A-8 in the same manner as in Example 2-1.

mp 87-90° C.; ¹H-NMR (CDCl₃) δ: 1.45 (s, 9H), 1.69-1.83 (m, 4H),1.84-1.94 (m, 2H), 2.08-2.18 (m, 2H), 2.19-2.26 (m, 2H), 2.41 (s, 3H),2.59 (t, 2H, J=6.8 Hz), 2.88-2.96 (m, 2H), 4.71 (tt, 1H, J=4.0 Hz, 12.0Hz), 5.92 (d, 1H, J=3.6 Hz), 6.19 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.96-7.02(m, 1H), 7.03-7.16 (m, 3H), 7.20-7.25 (m, 1H), 7.47-7.57 (m, 2H), 8.40(d, 1H, J=2.8 Hz); IR (KBr) cm⁻¹: 3449, 2930, 1713, 1664, 1591, 1471,1365, 1329, 1246, 1162, 1048, 1023; MS (ESI) m/z: 519 (MH⁺); Anal. Calcdfor C₃₀H₃₈N₄O₄.2/3H₂O: C, 67.90; H, 7.47; N, 10.56 Found: C, 67.77; H,7.50; N, 10.37.

EXAMPLE 2-9N-[1-(3-Cyclohexylpropyl)piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1B-1 in the same manner as in Example 2-1.

mp 249-252° C.; ¹H-NMR (DMSO-d₆) δ: 0.75-0.89 (m, 2H), 1.02-1.22 (m,6H), 1.27-1.40 (m, 4H), 1.53-1.69 (m, 5H), 1.70-1.80 (m, 2H), 1.89-2.00(m, 2H), 2.12-2.24 (m, 2H), 2.37 (s, 3H), 2.79-2.88 (m, 2H), 4.48 (tt,1H, J=3.9 Hz, 12.2 Hz), 5.46 (d, 1H, J=3.4 Hz), 6.28 (dd, 1H, J=1.5 Hz,3.4 Hz), 7.08 (d, 2H, J=8.3 Hz), 7.25 (d, 2H, J=8.3 Hz), 7.58 (d, 1H,J=1.5 Hz); IR (KBr) cm⁻¹: 2923, 1634, 1469, 1403, 1325, 769, 756, 734;MS (ESI) m/z: 409 (MH⁺).

EXAMPLE 2-10 Methyl[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetate

The title compound was synthesized from the compound obtained in Example1B-2 in the same manner as in Example 2-1.

mp 118-200° C.; ¹H-NMR (DMSO-d₆) δ: 1.25-1.48 (m, 10H), 1.62-1.80 (m,4H), 1.89-2.08 (m, 2H), 2.26 (s, 2H), 2.39 (s, 3H), 2.94-3.04 (m, 2H),3.05-3.20 (m, 2H), 3.44-3.56 (m, 2H), 3.59 (s, 3H), 4.75-4.87 (m, 1H),5.50 (d, 1H, J=3.4 Hz), 6.32 (dd, 1H, J=2.0 Hz, 3.4 Hz), 7.16 (d, 2H,J=7.8 Hz), 7.30 (d, 2H, J=7.8 Hz), 7.63 (d, 1H, J=2.0 Hz); IR (KBr)cm⁻¹: 3525, 3398, 2932, 2517, 2490, 1721, 1624, 1509, 1466, 1402, 1338,1307, 1204, 1190, 767, 759; MS (ESI) 467 m/z (MH⁺).

EXAMPLE 2-11N-[1-[2-[1-(2-Cyanoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1B-4 in the same manner as in Example 2-1.

¹H-NMR (DMSO-d₆) δ: 1.10-1.44 (m, 14H), 1.49-1.58 (m, 2H), 1.70-1.79 (m,2H), 1.92-2.02 (m, 2H), 2.10-2.20 (m, 2H), 2.27-2.34 (m, 2H), 2.37 (s,3H), 2.84-2.94 (m, 2H), 4.48 (tt, 1H, J=3.4 Hz, 12.2 Hz), 5.47 (d, 1H,J=3.4 Hz), 6.29 (dd, 1H, J=2.0 Hz, 3.4 Hz), 7.08 (d, 2H, J=8.3 Hz), 7.25(d, 2H, J=8.3 Hz), 7.59 (d, 1H, J=2.0 Hz).

EXAMPLE 2-123-[1-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]piperi-din-1-yl]methylcyclohexyl]propylacetate

The title compound was synthesized from the compound obtained in Example1C-1 in the same manner as in Example 2-1.

¹H-NMR (CDCl₃) δ: 1.14-1.65 (m, 16H), 1.77-1.87 (m, 2H), 2.00 (s, 3H),2.08 (s, 2H), 2.33-2.44 (m, 2H), 2.42 (s, 3H), 2.72-2.79 (m, 2H), 3.98(t, 2H, J=6.8 Hz), 4.63 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.93 (d, 1H, J=3.2Hz), 6.19 (dd, 1H, J=1.6 Hz, 3.2 Hz), 6.99 (d, 1H, J=8.0 Hz), 7.19-7.24(m, 1H), 7.53 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.14 (d, 1H, J=2.4 Hz).

EXAMPLE 2-13 Methyl1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]piperi-din-1-yl]ethyl]cyclohexanecarboxylate

The title compound was synthesized from the compound obtained in Example1D-1 in the same manner as in Example 2-1.

Free Form

¹H-NMR (CDCl₃) δ: 1.10-1.39 (m, 6H), 1.45-1.72 (m, 6H), 1.84-2.12 (m,6H), 2.18-2.30 (m, 2H), 2.37 (s, 3H), 2.87-2.99 (m, 2H), 3.62 (s, 3H),4.71 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.94 (d, 1H, J=2.4 Hz), 6.19 (dd, 1H,J=2.4 Hz, 3.6 Hz), 6.98 (d, 1H, J=8.0 Hz), 7.19-7.24 (m, 1H), 7.50 (dd,1H, J=2.4 Hz, 8.0 Hz), 8.37 (d, 1H, J=2.4 Hz).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.17-1.35 (m, 5H), 1.41-1.58 (m, 3H), 1.76-1.95 (m,6H), 1.97-2.06 (m, 2H), 2.36 (s, 3H), 2.82-2.93 (m, 2H), 3.01-3.15 (m,2H), 3.43-3.55 (m, 2H), 3.65 (s, 3H), 4.66-4.78 (m, 1H), 5.91 (d, 1H,J=3.6 Hz), 6.36 (dd, 1H, J=2.4 Hz, 3.6 Hz), 7.23 (d, 1H, J=8.0 Hz),7.54-7.58 (m, 1H), 7.73 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.37-8.41 (m, 1H);MS (ESI) m/z: 527 (MH⁺).

EXAMPLE 2-14N-[1-[3-[2-(Cyclohexylacetamido)phenyl]propyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1D-2 in the same manner as in Example 2-1.

Free Form

¹H-NMR (CDCl₃) δ: 0.79-1.00 (m, 2H), 1.04-1.35 (m, 3H), 1.55-1.87 (m,10H), 1.89-1.98 (m, 2H), 2.02-2.27 (m, 6H), 2.41 (s, 3H), 2.60 (t, 2H,J=6.4 Hz), 2.89-3.00 (m, 2H), 4.70 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.97 (d,1H, J=3.6 Hz), 6.20 (dd, 1H, J=2.0 Hz, 3.6 Hz), 6.95-7.01 (m, 1H),7.04-7.20 (m, 3H), 7.21-7.24 (m, 1H), 7.50-7.61 (m, 2H), 8.38-8.43 (m,1H), 8.99 (brs, 1H).

Hydrochloride

mp 116-119° C.; ¹H-NMR (DMSO-d₆) δ: 0.93-1.07 (m, 2H), 1.11-1.13 (m,3H), 1.57-1.94 (m, 10H), 1.96-2.07 (m, 2H), 2.22 (d, 2H, J=6.8 Hz), 2.36(s, 3H), 2.59 (t, 2H, J=8.0 Hz), 2.91-3.01 (m, 2H), 3.04-3.17 (m, 2H),3.41-3.51 (m, 2H), 4.70-4.81 (m, 1H), 5.90 (m, 1H, J=3.6 Hz), 6.36 (dd,1H, J=1.6 Hz, 3.6 Hz), 7.10-7.27 (m, 4H), 7.27-7.34 (m, 1H), 7.54-7.58(m, 1H), 7.73 (dd, 1H, J=2.0 Hz, 8.0 Hz), 8.37-8.41 (m, 1H), 9.25 (brs,1H), 9.53-9.65 (m, 1H); IR (KBr) cm⁻¹: 3426, 2923, 2849, 1644, 1523,1469, 1449, 1340, 1322, 1189, 1031, 755; MS (ESI) m/z: 543 (MH⁺).

EXAMPLE 2-15N-[1-(2-Cyclooctylethyl)piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1D-3 in the same manner as in Example 2-1.

Free Form

¹H-NMR (CDCl₃) δ: 1.18-1.74 (m, 19H), 1.88-1.97 (m, 2H), 2.02-2.13 (m,2H), 2.25-2.34 (m, 2H), 2.38 (s, 3H), 2.90-3.00 (m, 2H), 4.74 (tt, 1H,J=4.0 Hz, 12.0 Hz), 5.94 (d, 1H, J=3.6 Hz), 6.19 (dd, 1H, J=1.6 Hz, 3.6Hz), 6.99 (d, 1H, J=8.0 Hz), 7.21-7.24 (m, 1H), 7.50 (dd, 1H, J=2.4 Hz,8.0 Hz), 8.38 (d, 1H, J=2.4 Hz).

Hydrochloride

mp 107-110° C.; ¹H-NMR (DMSO-d₆) δ: 1.16-1.31 (m, 2H), 1.33-1.67 (m,15H), 1.80-1.94 (m, 2H), 1.96-2.06 (m, 2H), 2.37 (s, 3H), 2.91-3.01 (m,2H), 3.01-3.14 (m, 2H), 3.41-3.52 (m, 2H), 4.74 (tt, 1H, J=4.0 Hz, 12.0Hz), 5.90 (d, 1H, J=3.6 Hz), 6.35 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.24 (d,1H, J=8.0 Hz), 7.56 (d, 1H, J=1.6 Hz), 8.23 (dd, 1H, J=2.4 Hz, 8.0 Hz),8.39 (d, 1H, J=2.4 Hz), 9.65-9.77 (m, 1H); IR (KBr) cm⁻¹: 3425, 2922,2854, 1633, 1574, 1557, 1470, 1320, 1189, 769; MS (ESI) m/z: 424 (MH⁺);Anal. Calcd for C₂₆H₃₇N₃O₂HCl 5/2H₂O: C, 61.83; H, 8.58; N, 8.32. Found:C, 61.86; H, 8.36; N, 8.16.

EXAMPLE 2-16 Methyl4-[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]butyrate

The title compound was synthesized from the compound obtained inPreparation Example 1D-4 in the same manner as in Example 2-1.

Free Form

¹H-NMR (CDCl₃) δ: 1.16-1.29 (m, 6H), 1.31-1.44 (m, 8H), 1.46-1.72 (m,4H), 1.90-1.98 (m, 2H), 2.03-2.13 (m, 2H), 2.18-2.30 (m, 4H), 2.38 (s,3H), 2.93-3.02 (m, 2H), 3.67 (s, 3H), 4.74 (tt, 1H, J=4.0 Hz, 12.0 Hz),5.94 (d, 1H, J=3.6 Hz), 6.19 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.99 (d, 1H,J=8.0 Hz), 7.22 (d, 1H, J=1.6 Hz), 7.50 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.37(d, 1H, J=2.4 Hz).

Hydrochloride

mp 123-126° C.; ¹H-NMR (DMSO-d₆) δ: 1.10-1.29 (m, 6H), 1.31-1.49 (m,8H), 1.53-1.62 (m, 2H), 1.78-1.94 (m, 2H), 1.98-2.08 (m, 2H), 2.29 (t,2H, J=6.8 Hz), 2.37 (s, 3H), 2.86-2.96 (m, 2H), 3.03-3.15 (m, 2H),3.48-3.57 (m, 2H), 3.59 (s, 3H), 4.74 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.91(d, 1H, J=3.6 Hz), 6.36 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.24 (d, 1H, J=8.0Hz), 7.56 (d, 1H, J=1.6 Hz), 7.74 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.40 (d,1H, J=2.4 Hz), 9.41-9.56 (m, 1H); IR (KBr) cm⁻¹: 3425, 2928, 1729, 1633,1469, 1321, 1191, 1031, 769;

MS (ESI) m/z: 496 (MH⁺); Anal. Calcd for C₂₉H₄₂ClN₃O₃₄.2H₂O:C, 61.31; H,8.16; N, 7.40 Found: C, 61.11; H, 8.06; N, 7.34.

EXAMPLE 2-17 Triethyl3-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]-1,1,1-propanetricarboxylate

The title compound was synthesized from the compound obtained in Example1D-5 in the same manner as in Example 2-1.

Free Form

¹H-NMR (CDCl₃) δ: 1.20-1.46 (m, 13H), 1.28 (t, 9H, J=7.2 Hz), 1.53-1.70(m, 4H), 1.90-2.13 (m, 5H), 2.20-2.29 (m, 2H), 2.38 (s, 3H), 2.94-3.03(m, 2H), 4.25 (q, 6H, J=7.2 Hz), 4.74 (tt, 1H, J=4.0 Hz, 12.4 Hz), 5.93(d, 1H, J=3.6 Hz), 6.19 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.99 (d, 1H, J=8.4Hz), 7.20-7.24 (m, 1H), 7.47-7.53 (m, 1H), 8.38 (d, 1H, J=2.4 Hz).

Hydrochloride

mp 131-134° C.; ¹H-NMR (DMSO-d₆) δ: 1.15-1.28 (m, 4H), 1.20 (t, 9H,J=7.2 Hz), 1.29-1.47 (m, 8H), 1.53-1.63 (m, 2H), 1.77-1.95 (m, 4H),1.99-2.09 (m, 2H), 2.37 (s, 3H), 2.87-2.97 (m, 2H), 3.06-3.18 (m, 2H),3.46-3.58 (m, 2H), 4.19 (q, 6H, J=7.2 Hz), 4.76 (tt, 1H, J=4.0 Hz, 12.0Hz), 5.92 (d, 1H, J=3.6 Hz), 6.36 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.24 (d,H, J=8.0 Hz), 7.54-7.58 (m, 1H), 7.74 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.40(d, 1H, J=2.4 Hz), 9.13-9.25 (m, 1H); IR (KBr) cm⁻¹: 3451, 2932, 1755,1732, 1660, 1646, 1469, 1324, 1265, 1253, 1210, 773 cm⁻¹; MS (ESI) m/z:654 (MH⁺); Anal. Calcd for C₃₆H₅₂ClN₃O₈ 2H₂O:C, 59.53; H, 7.77; N, 5.79Found: C, 59.42; H, 7.50; N, 5.65.

EXAMPLE 2-18 Dimethyl3-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]-piperidin-1-yl]-ethyl]cyclohexyl]-1,1-propanedicarboxylate

The title compound was synthesized from the compound obtained in Example1D-6 in the same manner as in Example 2-1.

Free Form

¹H-NMR (CDCl₃): 1.15-1.45 (m, 14H), 1.45-1.59 (m, 2H), 1.67-1.90 (m,4H), 2.06-2.16 (m, 2H), 2.17-2.26 (m, 2H), 2.39 (s, 3H), 2.92-3.03 (m,2H), 3.26 (t, 1H, J=7.2 Hz), 3.74 (s, 6H), 4.72-4.83 (m, 1H), 5.30-5.40(m, 1H), 6.13 (dd, 1H, J=1.6 Hz, 3.2 Hz), 7.02 (d, 2H, J=8.0 Hz), 7.18(d, 2H, J=8.0 Hz), 7.33-7.38 (m, 1H); MS (ESI) m/z: 553 (MH⁺).

EXAMPLE 2-192-[2-[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,3-diacetoxypropane

The title compound was synthesized from the compound obtained in Example1D-7 in the same manner as in Example 2-1.

Free Form

¹H-NMR (CDCl₃) δ: 1.14-1.47 (m, 15H), 1.53-1.70 (m, 2H), 1.84-2.15 (m,6H), 2.05 (s, 6H), 2.16-2.27 (m, 2H), 2.38 (s, 3H), 2.92-3.04 (m, 2H),4.02 (dd, 1H, J=4.8 Hz, 11.6 Hz), 4.07 (dd, 2H, J=4.8 Hz, 9.8 Hz), 4.73(tt, 1H, J=4.0 Hz, 12.0 Hz), 5.94 (d, 1H, J=3.6 Hz), 6.19 (dd, 1H, J=1.6Hz, 3.6 Hz), 6.99 (d, 1H, J=8.0 Hz), 7.20-7.24 (m, 1H), 7.50 (dd, 1H,J=2.4 Hz, 8.0 Hz), 8.37 (d, 1H, J=2.4 Hz).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.10-1.66 (m, 17H), 1.78-1.95 (m, 2H), 1.97-2.09 (m,2H), 2.01 (s, 6H), 2.37 (s, 3H), 2.84-2.94 (m, 2H), 3.03-3.16 (m, 2H),3.47-3.56 (m, 2H), 3.78-4.07 (m, 4H), 4.69-4.80 (m, 1H), 5.91 (d, 1H,J=3.6 Hz), 6.36 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.24 (d, 1H, J=8.0 Hz),7.54-7.58 (m, 1H), 7.73 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.40 (d, 1H, J=2.4Hz), 9.50-9.71 (m, 1H); MS (ESI) m/z: 582 (MH⁺).

EXAMPLE 2-202-[2-[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,3-diacetoxypropane

The title compound was synthesized from the compound obtained in Example1D-8 in the same manner as in Example 2-1.

¹H-NMR (CDCl₃) δ: 1.15-1.30 (m, 8H), 1.31-1.66 (m, 10H), 1.81-1.94 (m,3H), 2.03-2.13 (m, 2H), 2.05 (s, 6H), 2.15-2.23 (m, 2H), 2.39 (s, 3H),2.92-3.00 (m, 2H), 4.01 (dd, 2H, J=6.4 Hz, 11.2 Hz), 4.07 (dd, 2H, J=5.2Hz, 11.2 Hz), 4.77 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.32-5.39 (m, 1H), 6.13(dd, 1H, J=1.6 Hz, 3.6 Hz), 7.01 (d, 2H, J=8.0 Hz), 7.18 (d, 2H, J=8.0Hz), 7.33-7.36 (m, 1H); M (ESI) m/z: 581 (MH⁺).

EXAMPLE 2-21N-[1-[2-[1-(4-Methoxymethoxy)-3-(methoxymethoxymethyl)butyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1D-9 in the same manner as in Example 2-1.

¹H-NMR (CDCl₃) δ: 1.19-1.46 (m, 16H), 1.54-1.67 (m, 2H), 1.70-1.79 (m,1H), 1.89-1.98 (m, 2H), 2.03-2.13 (m, 2H), 2.18-2.27 (m, 2H), 2.38 (s,3H), 2.92-3.02 (m, 2H), 3.36 (s, 6H), 3.46-3.56 (m, 4H), 4.61 (s, 4H),4.74 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.93 (d, 1H, J=3.6 Hz), 6.19 (dd, 1H,J=2.0 Hz, 3.6 Hz), 6.99 (d, 1H, J=8.4 Hz), 7.20-7.24 (m, 1H), 7.50 (dd,1H, J=2.4 Hz, 8.4 Hz), 8.38 (d, 1H, J=2.4 Hz); MS (ESI) m/z: 586 (MH⁺).

EXAMPLE 2-22N-[1-[2-[1-(2-Phenyl-1,3-dioxan-5-yl)cyclohexyl]ethyl]-piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1D-10 in the same manner as in Example 2-1.

¹H-NMR (CDCl₃) δ: 1.24-1.40 (m, 5H), 1.40-1.55 (m, 7H), 1.55-1.69 (m,2H), 1.91-2.01 (m, 2H), 2.08-2.26 (m, 3H), 2.27-2.35 (m, 2H), 2.37 (s,3H), 2.94-3.06 (m, 2H), 3.87 (t, 2H, J=11.2 Hz), 4.24 (dd, 2H, J=4.4 Hz,11.2 Hz), 4.75 (tt, 1H, J=4.4 Hz, 12.4 Hz), 5.36 (s, 1H), 5.94 (d, 1H,J=3.6 Hz), 6.19 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.99 (d, 1H, J=7.6 Hz),7.21-7.24 (m, 1H), 7.29-7.35 (m, 3H), 7.44-7.52 (m, 3H), 8.38 (d, 1H,J=2.4 Hz).

EXAMPLE 2-23N-[1-[2-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)cyclohexyl]ethyl]-piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1D-11 in the same manner as in Example 2-1.

¹H-NMR (CDCl₃) δ: 1.19-1.60 (m, 14H), 1.36 (s, 3H), 1.39 (s, 3H),1.81-1.92 (m, 2H), 1.95-2.07 (m, 1H), 2.08-2.18 (m, 2H), 2.22-2.31 (m,2H), 2.39 (s, 3H), 2.92-3.02 (m, 2H), 3.76 (dd, 2H, J=4.8 Hz, 11.6 Hz),3.84 (t, 2H, J=11.6 Hz), 4.78 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.30-5.40 (m,1H), 6.14 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.02 (d, 1H, J=8.0 Hz), 7.19 (d,2H, J=8.0 Hz), 7.33-7.38 (m, 1H); MS (ESI) m/z: 509 (MH⁺).

EXAMPLE 2-242-(Acetoxymethyl)-2-[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane

The title compound was synthesized from the compound obtained in Example1D-12 in the same manner as in Example 2-1.

¹H-NMR (CDCl₃) δ: 1.12-1.46 (m, 16H), 1.55-1.73 (m, 5H), 1.91-1.99 (m,2H), 2.01-2.12 (m, 1H), 2.04 (s, 3H), 2.06 (s, 6H), 2.16-2.24 (m, 2H),2.38 (s, 3H), 2.93-3.01 (m, 2H), 3.94 (s, 4H), 4.12 (t, 2H, J=7.2 Hz),4.68-4.79 (m, 1H), 5.93 (d, 1H, J=3.6 Hz), 6.19 (dd, 1H, J=1.6 Hz, 3.6Hz), 6.99 (d, 1H, J=8.0 Hz), 7.20-7.25 (m, 1H), 7.50 (dd, 1H, J=2.0 Hz,8.0 Hz), 8.38 (d, 1H, J=2.0 Hz); MS (ESI) m/z: 668 (MH⁺).

EXAMPLE 2-25 Methyl5,5-bis(benzoyloxymethyl)-7-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]heptanoate

The title compound was synthesized from the compound obtained in Example1D-13 in the same manner as in Example 2-1.

¹H-NMR (CDCl₃) δ: 1.14-1.55 (m, 19H), 1.61-1.82 (m, 7H), 2.03-2.13 (m,2H), 2.34 (t, 2H, J=7.2 Hz), 2.39 (s, 3H), 2.73-2.82 (m, 2H), 3.62 (s,3H), 4.26 (d, 2H, J=11.6 Hz), 4.31 (d, 2H, J=11.6 Hz), 4.57-4.69 (m,1H), 5.28-5.34 (m, 1H), 6.14 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.99 (d, 2H,J=8.0 Hz), 7.18 (d, 2H, J=8.0 Hz), 7.37 (d, 1H, J=1.6 Hz), 7.41-7.49 (m,4H), 7.56-7.64 (m, 2H), 7.98-8.05 (m, 4H).

EXAMPLE 2-26N-[1-[2-[1-(2-Cyanoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1B-3 in the same manner as in Example 2-1. Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.18-1.40 (m, 12H), 1.55-1.60 (m, 4H), 1.81-1.91 (m,2H), 2.03 (d, 2H, J=13.2 Hz), 2.37 (s, 3H), 2.43 (t, 2H, J=7.8 Hz), 2.91(m, 2H), 3.03-3.12 (m, 2H), 3.53 (d, 2H, J=12.2 Hz), 4.73 (t, 1H, J=12.2Hz), 5.87 (d, 1H, J=2.9 Hz), 6.38 (dd, 1H, J=1.9, 3.4 Hz), 7.27 (d, 1H,J=8.3 Hz), 7.59 (d, 1H, J=1.0 Hz), 7.75 (dd, 1H, J=2.0, 8.3 Hz), 8.41(d, 1H, J=2.0 Hz); IR (KBr) cm⁻¹: 3431, 2928, 2638, 2528, 2244, 1623,1593, 1469, 1400, 1339, 1229, 1190, 1030, 754; MS (ESI) m/z: 449 (MH⁺).

EXAMPLE 2-27N-[1-[2-[1-(2-Methanesulfonamidoethyl)cyclohexyl]ethyl]-piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1D-15 in the same manner as in Example 2-1.

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.19-1.25 (m, 4H), 1.32-1.48 (m, 8H), 1.64 (m, 2H),1.88 (q like, 2H), 2.03 (brd, 2H, J=12.7 Hz), 2.38 (s, 3H), 2.26 (s,2H), 2.91-3.00 (m, 7H), 3.10 (q like, 2H), 3.53 (d, 2H, J=11.3 Hz), 4.76(t like, 1H), 5.86 (d, 1H, J=3.5 Hz), 6.36 (m, 1H), 6.88-7.00 (m, 1H),7.26 (d, 1H, J=8.3 Hz), 7.58 (s, 1H), 7.75 (d, 1H, J=7.8 Hz), 8.41 (s,1H), 9.78-9.87 (m, 1H).

EXAMPLE 2-28N-(1-Cyclohexylpiperidin-4-yl)-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1E-1 in the same manner as in Example 2-1.

¹H-NMR (CDCl₃) δ: 0.99-1.33 (m, 5H), 1.49-1.66 (m, 2H), 1.71-1.89 (m,3H), 1.91-2.02 (m, 2H), 2.18-2.53 (m, 3H), 2.37 (s, 3H), 2.93-2.96 (m,2H), 4.71 (tt, 1H, J=4.0 Hz, 12.4 Hz), 5.92 (d, 1H, J=3.6 Hz), 6.18 (dd,1H, J=1.6 Hz, 3.6 Hz), 7.00 (d, 1H, J=8.0 Hz), 7.21-7.24 (m, 1H),7.48-7.52 (m, 1H), 8.37-8.39 (m, 1H).

Hydrochloride

mp 213-216° C.; ¹H-NMR (DMSO-d₆) δ: 1.01-1.15 (m, 1H), 1.16-1.42 (m,4H), 1.54-1.65 (m, 1H), 1.74-2.08 (m, 8H), 2.37 (s, 3H), 3.01-3.23 (m,3H), 3.38-3.42 (m, 2H), 4.78 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.87-5.89 (m,1H), 6.35 (dd, 1H, J=2.0 Hz, 7.2 Hz), 7.25 (d, 1H, J=8.2 Hz), 7.55-7.58(m, 1H), 7.74 (dd, 1H, J=2.0 Hz, 8.2 Hz), 8.38-8.41 (m, 1H); IR(KBr)cm⁻¹: 2641, 2502, 1652, 1644, 1620, 1464, 1319, 1191, 770; MS (ESI) m/z:368 (MH⁺); Anal. Calcd for C₂₂H₂₉N₃O₂.2HCl:C, 60.00; H, 7.09; N, 9.54.Found: C, 60.11; H, 7.23; N, 9.54.

EXAMPLE 2-29N-[1-[2-(Cyclohexylacetamido)benzyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1G-2 in the same manner as in Example 2-1.

Free Form

¹H-NMR (CDCl₃) δ: 0.81-0.96 (m, 2H), 1.07-1.32 (m, 4H), 1.53-1.86 (m,7H), 1.95-2.06 (m, 4H), 2.17-2.27 (m, 2H), 2.40 (s, 3H), 2.86-2.96 (m,2H), 3.56 (s, 2H), 4.78 (tt, 1H, J=4.0 Hz, 12.0 Hz), 6.01 (d, 1H, J=3.2Hz), 6.21 (dd, 1H, J=1.6 Hz, 3.2 Hz), 6.93-7.00 (m, 2H), 7.02-7.08 (m,1H), 7.21-7.28 (m, 2H), 7.52 (dd, 1H, J=2.4 Hz, 8.4 Hz), 8.24 (d, 1H,J=8.4 Hz), 8.41 (d, 1H, J=2.4 Hz), 10.77 (brs, 1H).

Hydrochloride

mp 141-144° C.; ¹H-NMR (DMSO-d₆) δ: 0.93-1.09 (m, 2H), 1.10-1.31 (m,3H), 1.56-2.06 (m, 10H), 2.27-2.39 (m, 2H), 2.35 (s, 3H), 3.14-3.27 (m,2H), 3.28-3.38 (m, 2H), 4.15-4.24 (m, 2H), 4.72-4.83 (m, 1H), 5.88 (d,1H, J=3.6 Hz), 6.35 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.21 (d, 1H, J=8.4 Hz),7.24-7.31 (m, 1H), 7.38-7.46 (m, 2H), 7.52-7.59 (m, 2H), 7.71 (dd, 1H,J=2.4 Hz, 8.4 Hz), 8.36 (d, 1H, J=2.4 Hz), 9.87 (brs, 1H), 9.95-10.05(m, 1H); IR (KBr) cm⁻¹: 3444, 2923, 2849, 1651, 1470, 1454, 1336, 1322,1189; MS (ESI) m/z: 515 (MH⁺); Anal. Calcd for C₃₁H₄₂Cl₂N₄O₄.H₂O:C,61.48; H, 6.99; N, 9.25.

Found: C, 61.63; H, 7.05; N, 9.14.

EXAMPLE 2-30 Methyl5,5-bis(benzoyloxymethyl)-7-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamide]piperidin-1-yl]ethyl]cyclohexyl]heptanoate

The title compound was synthesized from the compound obtained in Example1D-14 in the same manner as in Example 2-1.

¹H-NMR (CDCl₃) δ: 1.15-1.56 (m, 19H), 1.62-1.84 (m, 7H), 2.03-2.14 (m,2H), 2.34 (t, 2H, J=6.8 Hz), 2.38 (s, 3H), 2.74-2.84 (m, 2H), 3.62 (s,3H), 4.26 (d, 2H, J=11.2 Hz), 4.31 (d, 2H, J=11.2 Hz), 4.54-4.65 (m,1H), 5.87 (d, 1H, J=3.6 Hz), 6.19 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.97 (d,1H, J=8.4 Hz), 7.22-7.26 (m, 1H), 7.41-7.53 (m, 5H), 7.56-7.63 (m, 2H),7.97-8.05 (m, 4H), 8.38 (d, 1H, J=2.0 Hz).

EXAMPLE 2-312-[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexy]ethyl2-furancarboxylate

The title compound was synthesized from the compound obtained in Example1F-1 in the same manner as in Example 2-1.

Free Form

¹H-NMR (CDCl₃) δ: 1.24-1.52 (m, 12H), 1.54-1.68 (m, 2H), 1.69-1.77 (m,2H), 1.89-1.98 (m, 2H), 2.05-2.15 (m, 2H), 2.26-2.35 (m, 2H), 2.38 (s,3H), 2.93-3.03 (m, 2H), 4.73 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.94 (d, 1H,J=3.6 Hz), 6.19 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.49 (dd, 1H, 1.6 Hz, 3.6Hz), 6.99 (d, 1H, J=8.0 Hz), 7.18 (d, 1H, J=3.6 Hz), 7.21-7.24 (m, 1H),7.50 (dd, 1H, J=2.4 Hz, 8.0 Hz), 7.55-7.59 (m, 1H), 8.38 (d, 1H, J=2.4Hz).

Hydrochloride

mp 123-126° C.; ¹H-NMR (DMSO-d₆) δ: 1.22-1.48 (m, 10H), 1.61-1.72 (m,4H), 1.77-1.95 (m, 2H), 1.99-2.09 (m, 2H), 2.37 (s, 3H), 2.95-3.16 (m,4H), 3.47-3.60 (m, 2H), 4.28 (t, 2H, J=7.2 Hz), 4.68-4.79 (m, 1H), 5.92(d, 1H, J=3.2 Hz), 6.36 (dd, 1H, J=1.6 Hz, 3.2 Hz), 6.68 (dd, 1H, J=1.6Hz, 3.2 Hz), 7.22-7.28 (m, 2H), 7.56 (d, 1H, J=1.6 Hz), 7.74 (dd, 1H,J=2.4 Hz, 8.0 Hz), 7.92-7.96 (m, 1H), 8.40 (d, 1H, J=2.4 Hz), 9.33-9.47(m, 1H); IR (KBr) cm⁻¹: 3440, 2929, 2507, 1717, 1673, 1621, 1556, 1471,1303, 1174, 1122, 758; MS (ESI) m/z: 534 (MH⁺); Anal. Calcd forC₃₁H₄₁Cl₂N₃O₅.1/2H₂O: C, 60.48; H, 6.88; N, 6.83. Found: C, 60.60; H,6.99; N, 6.79.

EXAMPLE 2-32 tert-Butyl[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]ethyl]carbamate

The title compound was synthesized from the compound obtained in Example1G-1 in the same manner as in Example 2-1.

¹H-NMR (DMSO-d₆) δ: 1.16-1.26 (m, 4H), 1.27-1.40 (m, 10H), 1.36 (s, 9H),1.41-1.52 (m, 2H), 1.70-1.80 (m, 2H), 1.90-2.00 (m, 2H), 2.14-2.23 (m,2H), 2.35 (s, 3H), 2.80-2.91 (m, 4H), 4.43 (tt, 1H, J=3.9 Hz, 12.2 Hz),5.85 (d, 1H, J=3.4 Hz), 6.33 (dd, 1H, J=2.0 Hz, 3.4 Hz), 6.50-6.60 (m,1H), 7.16 (d, 1H, J=7.8 Hz), 7.68 (dd, 1H, J=2.4 Hz, 7.8 Hz), 8.35 (d,1H, J=2.4 Hz).

EXAMPLE 2-33N-[1-[2-[2-(Cyclohexylacetamido)phenyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1G-3 in the same manner as in Example 2-1.

Hydrochloride

mp 201-204° C.; ¹H-NMR (DMSO-d₆) δ: 0.95-1.09 (m, 2H), 1.10-1.32 (m,4H), 1.60-1.84 (m, 7H), 2.00-2.12 (m, 2H), 2.20-2.29 (m, 2H), 2.39 (s,3H), 2.88-2.98 (m, 2H), 3.12-3.24 (m, 4H), 3.50-3.60 (m, 2H), 4.78-4.89(m, 1H), 5.46-5.52 (m, 1H), 6.31-6.32 (m, 1H), 7.16-7.33 (m, 8H),7.62-7.63 (m, 1H), 9.39-9.40 (m, 1H); IR (KBr) cm⁻¹: 3426, 3216, 3174,2921, 2848, 2533, 2488, 1674, 1645, 1524, 1513, 1473, 1447, 1401, 1338,754; MS (ESI⁺) m/z: 528 (MH⁺).

EXAMPLE 2-34N-[1-[3-[2-(3-Cyclohexylpropionamido)phenyl]propyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example1G-4 in the same manner as in Example 2-1.

Hydrochloride

mp 113-117° C.; ¹H-NMR (DMSO-d₆) δ: 0.85-0.97 (m, 2H), 1.11-1.32 (m,4H), 1.44-1.53 (m, 2H), 1.58-1.80 (m, 7H), 1.84-1.94 (m, 2H), 1.97-2.08(m, 2H), 2.29-2.39 (m, 2H), 2.38 (s, 3H), 2.52-2.63 (m, 2H), 2.90-3.00(m, 2H), 3.07-3.12 (m, 2H), 3.40-3.52 (m, 2H), 4.75-4.89 (m, 1H),5.48-5.50 (m, 1H), 6.29-6.32 (m, 1H), 7.00-7.40 (m, 8H), 7.60-7.62 (m,1H), 9.26 (s, 1H); IR (KBr) cm⁻¹: 3432, 3246, 2932, 2849, 1686, 1635,1519, 1467, 1449, 1392, 1330, 1246, 1184, 1157, 761; MS (ESI⁺) m/z: 556(MH⁺).

EXAMPLE 2-351-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]piperi-din-1-yl]ethyl]cyclohexanecarboxylicacid

The title compound was synthesized from the compound obtained in Example1H-2 in the same manner as in Example 2-1.

Free Form

¹H-NMR (DMSO-d₆) δ: 1.07-1.35 (m, 5H), 1.38-1.57 (m, 7H), 1.70-1.80 (m,2H), 1.81-1.91 (m, 2H), 1.93-2.05 (m, 2H), 2.15-2.24 (m, 2H), 2.35 (s,3H), 2.80-2.92 (m, 2H), 4.44 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.84 (d, 1H,J=3.2 Hz), 6.33 (dd, 1H, J=1.6 Hz, 3.2 Hz), 7.17 (d, 1H, J=8.0 Hz),7.50-7.55 (m, 1H), 7.65-7.70 (m, 1H), 8.33-8.37 (m, 1H).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.16-1.38 (m, 5H), 1.42-1.58 (m, 3H), 1.77-1.92 (m,6H), 1.96-2.05 (m, 2H), 2.36 (s, 3H), 2.86-2.96 (m, 2H), 3.04-3.16 (m,2H), 3.44-3.53 (m, 2H), 4.73 (tt, 1H, J=3.6 Hz, 12.4 Hz), 5.90 (d, 1H,J=3.6 Hz), 6.36 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.24 (d, 1H, J=8.0 Hz), 7.57(d, 1H, J=1.6 Hz), 7.73 (dd, 1H, J=2.0 Hz, 8.0 Hz), 8.39 (d, 1H, J=2.0Hz), 9.59-9.73 (m, 1H); IR (KBr) cm⁻¹: 3417, 2934, 2858, 1713, 1633,1469, 1318, 1190, 1130, 1031, 769; MS (ESI) m/z: 440 (MH⁺).

EXAMPLE 2-36 tert-Butyl[2-[3-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]propyl]phenyl]carbamate

The title compound was synthesized from the compound obtained in Example1B-5 in the same manner as in Example 2-1.

¹H-NMR (CDCl₃) δ: 1.44 (s, 9H), 1.54-1.70 (m, 2H), 1.71-1.85 (m, 4H),2.07-2.19 (m, 2H), 2.23 (t, 2H, J=6.4 Hz), 2.42 (s, 3H), 2.57 (t, 2H,J=6.4 Hz), 2.84-2.96 (m, 2H), 4.73 (tt, 1H, J=4.0 Hz, 12.0 Hz),5.27-5.39 (m, 1H), 6.14 (dd, 1H, J=2.0 Hz, 3.6 Hz), 6.93-7.16 (m, 5H),7.16-7.25 (m, 2H), 7.31-7.37 (m, 1H), 7.45-7.56 (m, 1H), 8.00-8.38 (m,1H).

EXAMPLE 2-37 tert-Butyl[2-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]phenyl]carbamate

The title compound was synthesized from the compound obtained in Example1A-9 in the same manner as in Example 2-1.

¹H-NMR (CDCl₃) δ: 1.44 (s, 9H), 1.68-1.82 (m, 2H), 1.88-1.97 (m, 2H),2.21-2.32 (m, 2H), 2.41 (s, 3H), 2.53-2.60 (m, 2H), 2.64-2.71 (m, 2H),2.97-3.06 (m, 2H), 4.71 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.93 (d, 1H, J=3.6Hz), 6.20 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.94-7.09 (m, 3H), 7.14-7.20 (m,1H), 7.21-7.24 (m, 1H), 7.53 (dd, 1H, J=2.4 Hz, 8.0 Hz), 7.60-7.67 (m,1H), 8.40 (d, 1H, J=2.4 Hz); IR (KBr) cm⁻¹: 2945, 2815, 1718, 1640,1591, 1482, 1331, 1297, 1253, 1166, 1029, 761; M (ESI) m/z: 505 (MH⁺);Anal. Calcd for C₂₉H₃₆N₄O₄.1/2H₂O: C, 67.81; H, 7.26; N, 10.91. Found:C, 67.57; H, 7.16; N, 10.83.

EXAMPLE 3A-1[2-[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetamido]aceticacid

Ethyl[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetamido]acetate(221 mg) was dissolved in methanol (5 mL). A 2N aqueous sodium hydroxidesolution (2.1 mL) was added to the solution, and it was stirred at roomtemperature for 16 hours. The solution was neutralized by addition ofacetic acid (0.25 mL) (to pH of about 6). The solvent was distilled offunder reduced pressure, and the resulting residue was extracted with 20%ethanol/chloroform. The organic layer was dried over anhydrous magnesiumsulfate and the solvent was distilled off under reduced pressure to givethe title compound (170 mg).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.22-1.39 (m, 11H), 1.70-1.73 (m, 2H), 1.82-1.90 (m,2H), 1.97-2.01 (d like, 2H), 2.07 (s, 2H), 2.35 (s, 3H), 3.06-3.11 (m,4H), 3.47 (d, 2H, J=11.7 Hz), 3.59 (s, 2H), 4.74 (t like, 1H), 5.84 (d,1H, J=3.4 Hz), 6.36 (dd, 1H, J=1.5, 3.4 Hz), 7.26 (d, 1H, J=8.3 Hz),7.59 (s, 1H), 7.74 (d, 1H, J=8.3 Hz), 8.39 (s, 1H), 9.84-9.94 (m, 1H);IR (KBr) cm⁻¹: 3418, 2928, 2856, 2706, 1742, 1651, 1556, 1470, 1403,1384, 1319, 1210, 1189, 1034, 769; MS (ESI) m/z: 511 (MH⁺).

EXAMPLE 3A-23-[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]phenyl]acetamido]propionicacid

The title compound was synthesized from the compound obtained in Example4A-3 in the same manner as in Example 3A-1.

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.22-1.38 (m, 10H), 1.72 (m, 2H), 1.85-1.89 (d like,2H), 1.98-2.01 (m, 3H), 2.35 (s, 3H), 2.38-2.49 (m, 3H), 3.03-3.14 (m,4H), 3.21-3.24 (m, 2H), 3.46 (d like, 2H), 4.75 (t like, 1H), 5.85 (d,1H, J=4.0 Hz), 6.36 (d, 1H, J=1.5 Hz), 7.28 (d, 1H, J=7.8 Hz), 7.59 (s,1H), 7.79 (d, 1H, J=8.3 Hz), 8.11 (d like, 1H), 8.40 (s, 1H), 10.16-1026(m, 1H); IR (KBr) cm⁻¹: 3418, 2928, 2645, 1728, 1644, 1556, 1470, 1318,1189, 1029, 768; MS (ESI) m/z: 525 (MH⁺).

EXAMPLE 3A-3[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]aceticacid

The title compound was synthesized from the compound obtained in Example2-6 in the same manner as in Example 3A-1.

Free Form

mp 220-222° C. (dec); ¹H-NMR (DMSO-d₆) δ: 1.17-1.55 (m, 14H), 1.75-1.83(m, 2H), 2.05-2.14 (m, 4H), 2.28-2.36 (m, 5H), 2.93-3.00 (m, 2H),4.43-4.53 (m, 1H), 5.79 (d, 1H, J=3.5 Hz), 6.33 (dd, 1H, J=1.5 Hz, 3.5Hz), 7.18 (d, 1H, J=7.8 Hz), 7.55 (d, 1H, J=1.5 Hz), 7.70 (dd, 1H, J=2.0Hz, 7.8 Hz), 8.36 (d, 1H, J=2.0 Hz).

Hydrochloride

mp 120-130° C. (dec); ¹H-NMR (CDCl₃) δ: 1.30-1.55 (m, 10H), 1.90-1.98(m, 2H), 2.20-2.38 (m, 6H), 2.47 (s, 3H), 3.00-3.14 (m, 4H), 3.53-3.63(m, 2H), 4.95-5.05 (m, 1H), 6.21-6.28 (m, 2H), 7.22 (brs, 1H), 7.27-7.33(m, 1H), 7.81-7.87 (m, 1H), 8.45 (brs, 1H), 11.59 (brs, 1H).

EXAMPLE 3A-4[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclopentyl]aceticacid

The title compound was synthesized from the compound obtained in Example2-7 in the same manner as in Example 3A-1.

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.38-1.57 (m, 8H), 1.72-1.82 (m, 4H), 2.00-2.03 (m,2H), 2.18 (s, 1H), 2.35 (s, 3H), 2.99-3.09 (m, 4H), 3.48 (d, 2H, J=6.8Hz), 4.70-4.77 (m, 1H), 5.87 (d, 2H, J=2.9 Hz), 6.37 (dd, 1H, J=5.4 Hz),7.26 (d, 1H, J=7.8 Hz), 7.59 (d, 1H, J=1.4 Hz), 7.74 (d, 1H, J=7.3 Hz),8.40 (s, H); MS (ESI) m/z: 440 (MH⁺).

EXAMPLE 3B-1[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]eth-yl]cyclohexyl]aceticacid

To methyl[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetate(0.5241 g) and lithium hydroxide monohydrate (0.94 g) were added1,4-dioxane (20 mL) and water (5 mL). The resulting suspension wasstirred at room temperature for 3 days. The reaction solution wasbrought to dryness and the residue was diluted with water. Acetic acid(1.0 mL) was then added to the solution and it was extracted with 25%ethanol/chloroform. The extract was dried over (MgSO₄) and the solventwas distilled off under reduced pressure. The resulting residue waspurified by chromatography (silica gel, 10% methanol/chloroform) to givethe title compound (0.36 g), which was then converted to itshydrochloride by hydrochloric acid to give the title compound as a whitesolid (0.3805 g).

Hydrochloride

mp 235-240° C.; ¹H-NMR (DMSO-d₆) δ: 25-1.49 (m, 10H), 1.63-1.81 (m, 4H),1.97-2.06 (m, 2H), 2.16 (s, 2H), 2.38 (s, 3H), 2.93-3.04 (m, 2H),3.05-3.19 (m, 2H), 3.40-3.53 (m, 2H), 4.73-4.86 (m, 1H), 5.50 (d, 1H,J=3.4 Hz), 6.32 (dd, 1H, J=2.0 Hz, 3.4 Hz), 7.16 (d, 1H, J=7.8 Hz), 7.30(d, 1H, J=7.8 Hz), 7.63 (d, 1H, J=2.0 Hz); IR (KBr) cm⁻¹: 2931, 2650,1721, 1642, 1151, 1469, 1396, 1343, 1316, 1235, 1188, 1129, 1032, 948,770, 757; MS (ESI) 453 m/z:(MH⁺).

EXAMPLE 3B-23-[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]-1,1-propanedicarboxylicacid

The title compound was synthesized from the compound obtained in Example2-18 in the same manner as in Example 3B-1.

Free Form

¹H-NMR (CDCl₃): 1.03-1.66 (m, 18H), 1.72-1.87 (m, 1H), 1.97-2.21 (m,3H), 2.41 (s, 3H), 2.75-3.03 (m, 3H), 3.48-3.69 (m, 2H), 4.79-4.99 (m,1H), 5.88-6.02 (m, 1H), 6.14-6.29 (m, 1H), 6.90-7.02 (m, 1H), 7.48-7.64(m, 1H), 8.30-8.44 (m, 1H).

Hydrochloride

mp 136-139° C.; ¹H-NMR (DMSO-d₆) δ: 1.12-1.29 (m, 6H), 1.30-1.48 (m,6H), 1.53-1.70 (m, 4H), 1.78-1.94 (m, 2H), 1.98-2.09 (m, 2H), 2.37 (s,3H), 2.86-2.97 (m, 2H), 3.02-3.22 (m, 3H), 3.48-3.58 (m, 2H), 4.68-4.80(m, 1H), 5.91 (d, 1H, J=3.6 Hz), 6.36 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.24(d, 1H, J=8.4 Hz), 7.54-7.57 (m, 1H), 7.73 (dd, 1H, J=2.4 Hz, 8.4 Hz),8.38-8.42 (m, 1H), 9.35-9.51 (m, 1H), 12.29-12.85 (m, 2H); IR (KBr)cm⁻¹: 3424, 2928, 1726, 1633, 1469, 1402, 1339, 1229, 1192, 755; MS(ESI) m/z: 526 (MH⁺).

EXAMPLE 3B-34-[2-[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetamido]butyricacid

The title compound was synthesized from the compound obtained in Example4B-3 in the same manner as in Example 3B-1.

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.20-1.50 (m, 10H), 1.59-1.80 (m, 6H), 1.98-2.08 (m,4H), 2.19-2.24 (m, 2H), 2.38 (s, 3H), 3.00-3.18 (m, 6H), 3.44-3.55 (m,2H), 4.75-4.88 (m, 1H), 5.50 (d, 1H, J=3.4 Hz), 6.32 (dd, 1H, J=1.5 Hz,3.4 Hz), 7.15 (d, 2H, J=8.3 Hz), 7.29 (d, 2H, J=8.3 Hz), 7.62 (d, 1H,J=1.5 Hz), 7.90-7.96 (m, 1H); IR (NaCl film) cm⁻¹: 3387, 2928, 2859,1719, 1637, 1630, 1468, 757, 734; MS (ESI) m/z: 538 (MH⁺).

EXAMPLE 3B-42-[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetyliminodiaceticacid

The title compound was synthesized from the compound obtained in Example4C-1 in the same manner as in Example 3B-1.

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.25-1.50 (m, 10H), 1.75-1.96 (m, 4H), 1.98-2.06 (m,2H), 2.15-2.28 (m, 2H), 2.37 (s, 3H), 2.90-3.12 (m, 4H), 3.40-3.52 (m,2H), 3.60-3.70 (m, 2H), 4.20-4.40 (m, 2H), 4.68-4.80 (m, 1H), 5.89 (d,1H, J=3.4 Hz), 6.35 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.23 (d, 1H, J=7.8 Hz),7.56 (d, 1H, J=1.5 Hz), 7.72-7.75 (m, 1H), 8.39-8.40 (m, 1H); IR (KBr)cm⁻¹: 3444, 1738, 1634, 1469, 1406; MS (ESI) 569 m/z: (MH⁺).

EXAMPLE 3B-5N-[1-[2-[1-[N-[Tris(hydroxymethyl)methyl]carbamoylmethyl]cyclohexyl]ethyl]piperidin-1-yl]-N-(5-methylpyridin-4-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example4B-5 in the same manner as in Example 3B-1.

Hydrochloride

mp 83-88° C. (dec.); ¹H-NMR (DMSO-d₆) δ: 0.80-0.98 (m, 2H), 1.09-1.28(m, 3H), 1.55-1.77 (m, 6H), 1.98-2.12 (m, 4H), 2.36 (s, 3H), 3.00-3.08(m, 2H), 3.20-3.33 (m, 2H), 3.39-3.50 (m, 2H), 3.54-3.67 9m, 2H),4.39-4.50 (m, 2H), 4.73-4.84 (m, 1H), 5.90 (d, 1H, J=3.9 Hz), 6.36 (dd,1H, J=2.0 Hz, 3.9 Hz), 7.06 (t, 1H, J=7.8 Hz), 7.16 (d, 1H, J=7.8 Hz),7.25 (d, 1H, J=7.8 Hz), 7.40-7.52 (m, 2H), 7.56 (d, 1H, J=2.0 Hz), 7.73(dd, 1H, J=2.0 Hz, 7.8 Hz), 8.18-8.26 (m, 1H), 8.39 (d, 1H, J=2.0 Hz);IR (KBr) cm⁻¹: 3426, 2923, 2849, 1643, 1470, 1448, 1317, 755; MS (ESI)m/z: 557 (MH⁺).

EXAMPLE 3B-6N-[(1-Carboxymethylcyclohexyl)acetyl]-N-[2-[2-[4-[N-(5-meth-ylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]-phenyl]aminoaceticacid

The title compound was synthesized from the compound obtained in Example5B-5 in the same manner as in Example 3B-1.

Hydrochloride

mp 146-149° C.; ¹H-NMR (DMSO-d₆) δ: 1.09-1.48 (m, 1H), 1.86-2.19 (m,6H), 2.27-2.40 (m, 1H), 2.37 (s, 3H), 2.55-2.70 (m, 1H), 2.86-3.07 (m,2H), 3.10-3.29 (m, 4H), 3.41-3.98 (m, 3H), 4.70-4.83 (m, 1H), 5.96 (d,1H, J=3.6 Hz), 6.35 (dd, 1H, J=2.0 Hz, 3.6 Hz), 7.23 (d, 1H, J=8.4 Hz),7.31-7.46 (m, 4H), 7.51-7.55 (m, 1H), 7.68-7.75 (m, 1H), 8.35-8.41 (m,1H), 9.87-10.12 (m, 1H); IR (KBr) cm⁻¹: 3425, 2929, 1727, 1644, 1469,1403, 1388, 1192, 770; MS (ESI) m/z: 645 (MH⁺).

EXAMPLE 3B-73-[2-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]phenyl]-5-cyclohexylhydantoicacid

The title compound was synthesized from the compound obtained in Example5B-8 in the same manner as in Example 3B-1.

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 0.92-1.37 (m, 4H), 1.46-2.15 (m, 10H), 2.37 (s, 3H),2.87-3.04 (m, 2H), 3.10-3.60 (m, 6H), 3.76-3.94 (m, 1H), 4.29-4.46 (m,2H), 4.71-4.86 (m, 1H), 5.87-5.95 (m, 1H), 6.33-6.39 (m, 1H), 7.25 (d,1H, J=8.0 Hz), 7.30-7.46 (m, 4H), 7.56 (brs, 1H), 7.70-7.77 (m, 1H),8.36-8.43 (m, 1H), 9.67-10.14 (m, 1H); IR (KBr) cm⁻¹: 3427, 2931, 2854,1703, 1644, 1469, 1386, 1339, 1190, 756; MS (ESI) m/z: 588 (MH⁺); Anal.Calcd for C₃₃H₄₂ClN₅O₆.1/2H₂O: C, 62.60; H, 6.85; N, 11.06. Found: C,62.68; H, 6.89; N, 11.01.

EXAMPLE 3C-14-[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]butyricacid

To a solution of methyl4-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]butyrate(210 mg) in methanol (10 mL) was added a 3N aqueous sodium hydroxidesolution (1.4 mL) at room temperature. After stirring the solution atroom temperature for 3 hours, a 3N aqueous sodium hydroxide solution(0.7 mL) was added thereto at room temperature. The solution was stirredat room temperature for 2 hours. Water (5 mL) and acetic acid (0.36 mL)were then added to the solution and it was concentrated under reducedpressure to distill off the methanol. The solution was extracted with20% ethanol/chloroform. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure to give the titlecompound (180 mg).

Free Form

¹H-NMR (CDCl₃): 1.14-1.30 (m, 6H), 1.32-1.46 (m, 8H), 1.48-1.56 (m, 2H),1.82-2.01 (m, 4H), 2.05-2.11 (m, 2H), 2.26 (s, 3H), 2.40-2.51 (m, 2H),2.57-2.66 (m, 2H), 3.34-3.44 (m, 2H), 4.74-4.87 (m, 1H), 5.96 (d, 1H,J=3.6 Hz), 6.20 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.99 (d, 1H, J=8.4 Hz), 7.23(d, 1H, J=1.6 Hz), 7.52 (dd, 1H, J=2.4 Hz, 8.4 Hz), 8.38 (d, 1H, J=2.4Hz).

Hydrochloride

mp 134-137° C.; ¹H-NMR (DMSO-d₆) δ: 1.11-1.47 (m, 14H), 1.52-1.64 (m,2H), 1.79-1.95 (m, 2H), 1.97-2.08 (m, 2H), 2.19 (t, 2H, J=7.2 Hz), 2.37(s, 3H), 2.86-2.97 (m, 2H), 3.02-3.15 (m, 2H), 3.47-3.57 (m, 2H), 4.74(tt, 1H, J=4.0 Hz, 12.0 Hz), 5.91 (d, 1H, J=3.6 Hz), 6.36 (dd, 1H, J=1.6Hz, 3.6 Hz), 7.24 (d, 1H, J=8.4 Hz), 7.56 (d, 1H, J=1.6 Hz), 7.74 (dd,1H, J=2.4 Hz, 8.4 Hz), 8.36-8.42 (m, 1H), 9.65-9.79 (m, 1H) IR (KBr)cm⁻¹: 3426, 2928, 1714, 1633, 1470, 1385, 1322, 1191, 768; MS (ESI) m/z:482 (MH⁺).

EXAMPLE 3C-25,5-Bis(hydroxymethyl)-7-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]heptanoicacid

The title compound was synthesized from the compound obtained in Example2-25 in the same manner as in Example 3C-1.

¹H-NMR (DMSO-d₆) δ: 0.90-1.28 (m, 10H), 1.30-1.61 (m, 10H), 1.77-1.93(m, 2H), 1.95-2.07 (m, 2H), 2.15 (t, 2H, J=7.6 Hz), 2.37 (s, 3H),2.87-2.98 (m, 2H), 3.00-3.13 (m, 2H), 3.18 (d, 2H, J=10.8 Hz), 3.22 (d,2H, J=10.8 Hz), 3.46-3.56 (m, 2H), 4.74 (tt, 1H, J=4.0 Hz, 12.0 Hz),5.91 (d, 1H, J=3.6 Hz), 6.36 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.24 (d, 1H,J=8.0 Hz), 7.56 (d, 1H, J=1.6 Hz), 7.73 (dd, 1H, J=2.4 Hz, 8.0 Hz),8.36-8.42 (m, 1H), 9.33-9.50 (m, 1H).

EXAMPLE 3C-35,5-Bis(hydroxymethyl)-7-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]heptanoicacid

The title compound was synthesized from the compound obtained in Example2-30 in the same manner as in Example 3C-1.

Free Form

¹H-NMR (CDCl₃) δ: 0.99-1.47 (m, 18H), 1.50-1.62 (m, 2H), 1.74-1.98 (m,4H), 1.99-2.08 (m, 2H), 2.40 (s, 3H), 2.58 (t, 2H, J=12.0 Hz), 2.69-2.85(m, 2H), 3.30-3.55 (m, 6H), 4.82-4.94 (m, 1H), 5.36 (d, 1H, J=3.2 Hz),6.15 (dd, 1H, J=1.6 Hz, 3.2 Hz), 6.99 (d, 2H, J=8.0 Hz), 7.21 (d, 2H,J=8.0 Hz), 7.37 (d, 1H, J=1.6 Hz).

EXAMPLE 3C-4N-[1-[2-(1-(2-Hydroxyethyl)cyclohexyl)ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example2-31 in the same manner as in Example 3C-1.

Free Form

¹H-NMR (CDCl₃): 1.19-1.32 (m, 4H), 1.32-1.48 (m, 8H), 1.50-1.64 (m, 4H),1.89-1.98 (m, 2H), 2.06-2.16 (m, 2H), 2.24-2.31 (m, 2H), 2.38 (s, 3H),2.95-3.02 (m, 2H), 3.61 (t, 2H, J=6.8 Hz), 4.72 (tt, 1H, J=4.0 Hz, 12.0Hz), 5.92 (d, 1H, J=3.6 Hz), 6.19 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.98 (d,1H, J=8.0 Hz), 7.20-7.24 (m, 1H), 7.50 (dd, 1H, J=2.4 Hz, 8.0 Hz),8.35-8.40 (m, 1H).

Hydrochloride

¹H-NMR (DMSO-d₆) δ 1.20-1.30 (m, 4H), 1.31-1.46 (m, 8H), 1.56-1.67 (m,2H), 1.79-1.94 (m, 2H), 1.98-2.07 (m, 2H), 2.37 (s, 3H), 2.90-3.02 (m,2H), 3.02-3.15 (m, 2H), 3.44 (t, 2H, J=7.6 Hz), 3.47-3.56 (m, 2H), 4.74(tt, 1H, J=4.0 Hz, 12.0 Hz), 5.91 (d, 1H, J=3.6 Hz), 6.36 (dd, 1H, J=1.6Hz, 3.6 Hz), 7.24 (d, 1H, J=8.4 Hz), 7.54-7.57 (m, 1H), 7.73 (dd, 1H,J=2.4 Hz, 8.4 Hz), 8.37-8.41 (m, 1H), 9.44-9.59 (m, 1H); IR (KBr) cm⁻¹:3425, 2927, 2857, 1633, 1593, 1574, 1469, 1402, 1339, 1191, 1034, 754;MS (ESI) m/z: 440 (MH⁺); Anal. Calcd for C₂₆H₃₈ClN₃O₃ 2H₂O: C, 60.98; H,8.27; N, 8.21. Found: C, 61.08; H, 8.39; N, 8.05.

EXAMPLE 3C-51-[N-[2-[2-[4-[N-(5-Methylpyrydin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]phenyl]carbamoylmethyl]cyclohexylaceticacid

The title compound was synthesized from the compound obtained in Example5B-4 in the same manner as in Example 3C-1.

Free Form

¹H-NMR (CDCl₃) δ: 1.36-1.63 (m, 10H), 1.89-2.12 (m, 4H), 2.38 (s, 3H),2.41 (s, 2H), 2.53-2.69 (m, 4H), 3.37-3.46 (m, 2H), 4.77-4.89 (m, 1H),5.96 (d, 1H, J=3.6 Hz), 6.21 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.94 (d, 1H,J=8.0 Hz), 7.01-7.12 (m, 2H), 7.12-7.29 (m, 2H), 7.52 (dd, 1H, J=2.4 Hz,8.0 Hz), 7.93 (d, 1H, J=7.6 Hz), 8.38 (d, 1H, J=2.4 Hz), 10.03-10.19 (m,1H).

Hydrochloride

mp 138-141° C.; ¹H-NMR (DMSO-d₆) δ: 1.32-1.60 (m, 10H), 1.82-1.97 (m,2H), 2.02-2.12 (m, 2H), 2.38 (s, 3H), 2.52-2.62 (m, 4H), 2.90-3.00 (m,2H), 3.10-3.25 (m, 4H), 3.49-3.60 (m, 2H), 4.72-4.85 (m, 1H), 5.91 (d,1H, J=3.6 Hz), 6.36 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.14-7.41 (m, 5H),7.53-7.59 (m, 1H), 7.71-7.78 (m, 1H), 8.36-8.44 (m, 1H), 9.37-9.46 (m,1H), 9.68-9.83 (m, 1H); IR (KBr) cm⁻¹: 3444, 2929, 1714, 1633, 1470,1454, 1403, 1342, 1192, 756; M (ESI) m/z: 587 (MH⁺).

EXAMPLE 3D-1N-[1-(1-(3-Hydroxypropyl)cyclohexylmethyl)piperdin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

To a solution of acetic acid3-[1-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperi-din-1-yl]methyl]cyclohexyl]propylester (180 mg) in methanol (10 mL) was added potassium carbonate (10 mg)at room temperature. After stirring the solution at room temperature for16 hours, it was concentrated under reduced pressure. Water was added tothe residue and it was extracted with chloroform. The organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by chromatography (NH silica gel,hexane:ethyl acetate=2:8) to give the title compound (180 mg).

Free Form

¹H-NMR (CDCl₃) δ: 1.15-1.49 (m, 14H), 1.50-1.64 (m, 2H), 1.79-1.88 (m,2H), 2.12 (s, 2H), 2.27-2.38 (m, 2H), 2.41 (s, 3H), 2.78-2.86 (m, 2H),3.55 (t, 2H, J=6.4 Hz), 4.64 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.91 (d, 1H,J=3.6 Hz), 6.19 (dd, 1H, J=2.0 Hz, 3.6 Hz), 6.99 (d, 1H, J=8.0 Hz), 7.22(d, 1H, J=2.0 Hz), 7.53 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.41 (d, 1H, J=2.4Hz).

Hydrochloride

mp 113-116° C.; ¹H-NMR (DMSO-d₆) δ: 1.20-1.54 (m, 14H), 1.88-2.17 (m,4H), 2.37 (s, 3H), 2.89-3.02 (m, 2H), 3.26-3.43 (m, 4H), 3.45-3.55 (m,2H), 4.59-4.85 (m, 1H), 5.86-5.96 (m, 1H), 6.33-6.38 (m, 1H), 7.23-7.29(m, 1H), 7.53-7.58 (m, 1H), 7.70-7.78 (m, 1H), 8.29-8.43 (m, 2H); IR(KBr) cm⁻¹: 3420, 2933, 2861, 1627, 1559, 1469, 1402, 1324, 1191, 769;MS (ESI) m/z: 440 (MH⁺); Anal. Calcd for C₂₆H₃₈C1N₃O₃5/2H₂O: C, 59.93;H, 8.32; N, 8.06. Found: C, 60.14; H, 8.32; N, 8.06.

EXAMPLE 3D-2N-[1-[2-[1-(4-Hydroxy-3-hydroxymethylbutyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example2-20 in the same manner as in Example 3D-1.

Free Form

¹H-NMR (CDCl₃) δ: 1.10-1.28 (m, 8H), 1.31-1.44 (m, 8H), 1.46-1.66 (m,3H), 1.79-1.90 (m, 2H), 2.03-2.14 (m, 2H), 2.16-2.25 (m, 2H), 2.40 (s,3H), 2.92-3.01 (m, 2H), 3.62 (dd, 2H, J=7.2 Hz, 10.8 Hz), 3.77 (dd, 2H,J=3.2 Hz, 10.8 Hz), 4.74 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.32-5.39 (m, 1H),6.14 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.02 (d, 2H, J=8.0 Hz), 7.19 (d, 2H,J=8.0 Hz), 7.35 (d, 1H, J=1.6 Hz).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.09-1.28 (m, 8H), 1.29-1.46 (m, 7H), 1.51-1.63 (m,2H), 1.65-1.80 (m, 2H), 1.94-2.07 (m, 2H), 2.38 (s, 3H), 2.82-2.96 (m,2H), 3.02-3.18 (m, 2H), 3.32-3.57 (m, 6H), 4.73-4.85 (m, 1H), 5.44-5.55(m, 1H), 6.31 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.15 (d, 2H, J=8.0 Hz), 7.29(d, 2H, J=8.0 Hz), 7.62 (d, 1H, J=1.6 Hz), 9.56-9.77 (m, 1H); IR (KBr)cm⁻¹: 3406, 2926, 2859, 1633, 1604, 1511, 1469, 1403, 1341, 1189, 1032,757; MS (ESI) m/z: 497 (MH⁺); Anal. Calcd for C₃₀H₄₅ClN₂O₄.1/2H₂O: C,66.46; H, 8.55; N, 5.17. Found: C, 66.43; H, 8.71; N, 5.01.

EXAMPLE 3D-3N-[1-[2-[1-[5-Hydroxy-3,3-bis(hydroxymethyl)pentyl]cyclohex-yl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furan-carboxamide

The title compound was synthesized from the compound obtained in Example2-24 in the same manner as in Example 3D-1.

Free Form

¹H-NMR (CDCl₃) δ: 1.07-1.29 (m, 8H), 1.32-1.46 (m, 8H), 1.55-1.74 (m,4H), 1.87-1.96 (m, 2H), 2.02-2.13 (m, 2H), 2.17-2.26 (m, 2H), 2.39 (s,3H), 2.94-3.02 (m, 2H), 3.47 (d, 2H, J=10.8 Hz), 3.51 (d, 2H, J=10.8Hz), 3.73 (t, 2H, J=5.6 Hz), 4.63-4.75 (m, 1H), 5.93 (d, 1H, J=3.6 Hz),6.19 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.99 (d, 1H, J=8.4 Hz), 7.20-7.24 (m,1H), 7.51 (dd, 1H, J=2.4 Hz, 8.4 Hz), 8.38 (d, 1H, J=2.4 Hz).

Hydrochloride

mp 102-105° C.; ¹H-NMR (DMSO-d₆) δ: 1.01-1.18 (m, 4H), 1.19-1.28 (m,4H), 1.30-1.45 (m, 8H), 1.49-1.59 (m, 2H), 1.75-1.92 (m, 2H), 1.98-2.08(m, 2H), 2.37 (s, 3H), 2.87-3.01 (m, 2H), 3.01-3.13 (m, 2H), 3.15-3.35(m, 4H), 3.43-3.56 (m, 4H), 4.69-4.80 (m, 1H), 5.92 (d, 1H, J=3.6 Hz),6.36 (dd, 1H, J=1.2 Hz, 3.6 Hz), 7.24 (d, 1H, J=8.0 Hz), 7.56 (d, 1H,J=1.2 Hz), 7.73 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.40 (d, 1H, J=2.4 Hz),9.02-9.16 (m, 1H); IR (KBr) cm⁻¹: 3388, 2929, 1643, 1470, 1402, 1338,1031, 754; MS (ESI) m/z: 542 (MH⁺); Anal. Calcd for C₃₁H₄₈ClN₃O₅4/5H₂O:C, 62.83; H, 8.44; N, 7.09. Found: C, 62.74; H, 8.45; N, 7.01.

EXAMPLE 3E-12-[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]acetylimino-N,N-bis(acetyliminodiacetate)

Tetraethyl2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]-acetylimino-N,N-bis(acetyliminodiaceticacid) (0.2597 g) was dissolved in 6N hydrochloric acid (20 mL). Thesolvent was then distilled off under reduced pressure. This procedurewas repeated twice. The residue was freeze-dried to give thehydrochloride of the title compound (0.2322 g).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.25-1.50 (m, 10H), 1.62-1.86 (m, 4H), 1.97-2.07 (m,2H), 2.08 (s, 2H), 2.38 (s, 3H), 2.87-2.97 (m, 2H), 3.00-3.13 (m, 2H),3.41-3.54 (m, 2H), 3.98-4.30 (12H), 4.74-4.84 (m, 1H), 5.51 (d, 1H,J=3.4 Hz), 6.32 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.16 (d, 2H, J=8.3 Hz), 7.30(d, 2H, J=8.3 Hz), 7.62 (d, 1H, J=1.5 Hz); IR (NaCl film) cm⁻¹: 2930,2859, 1736, 1637, 1469, 1406, 1190; MS (ESI) m/z: 798 (MH⁺).

EXAMPLE 3E-2N-[1-[2-[1-[N,N-Bis[N-[tris(hydroxymethyl)methyl]carbamoylmethyl]carbamoylmethyl]cyclohexyl]ethyl]piperidine-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example4B-6 in the same manner as in Example 3E-1.

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.20-1.53 (m, 12H), 1.72-1.97 (m, 4H), 1.98-2.07 (m,2H), 2.14-2.24 (m, 2H), 2.37 (s, 3H), 2.90-3.20 (m, 4H), 3.30-4.50 (brm,16H), 4.69-4.82 (m, 1H), 5.90 (d, 1H, J=3.4 Hz), 6.35 (dd, 1H, J=1.5 Hz,3.4 Hz), 7.24 (d, 1H, J=7.8 Hz), 7.55 (d, 1H, J=1.5 Hz), 7.60-7.77 (m,3H), 8.38-8.40 (m, 1H); IR (NaCl film) cm⁻¹: 3342, 2927, 2854, 1734,1647, 1636, 1466, 1458, 1398, 1187, 1059, 754; MS (ESI) m/z: 775 (MH⁺).

EXAMPLE 3E-3N-[2-[3-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]-propyl]phenyl]-N-(3-cyclohexylpropionyl)aminobutyricacid

The title compound was synthesized from the compound obtained in Example5B-3 in the same manner as in Example 3E-1.

Hydrochloride

mp 105-115° C.; ¹H-NMR (DMSO-d₆) δ: 0.64-0.77 (m, 2H), 0.95-2.08 (m,21H), 2.16-2.22 (m, 2H), 2.38 (s, 3H), 2.41-2.51 (m, 2H), 2.94-3.22 (m,5H), 3.44-3.56 (m, 2H), 3.97-4.06 (m, 1H), 4.76-4.86 (m, 1H), 5.49 (d,1H, J=3.4 Hz), 6.31 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.16 (d, 2H, J=8.3 Hz),7.15-7.20 (m, 1H), 7.30 (d, 2H, J=8.3 Hz), 7.30-7.48 (m, 3H), 7.62 (d,1H, J=1.5 Hz); IR (KBr) cm⁻¹: 3433, 2923, 2850, 1725, 1639, 1470, 1450,1405, 757, 736; MS (ESI) m/z: 642 (MH⁺).

EXAMPLE 3F-1N-[2-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]phenyl]-N-(cyclohexylacetyl)aminoaceticacid

tert-ButylN-[2-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]phenyl]-N-(cyclohexylacetyl)aminoacetate(0.1318 g) was dissolved in a 4N hydrochloric acid/1,4-dioxane solution(6.0 mL). The solution was stirred at room temperature for 3 days. Thesolvent was distilled off under reduced pressure. The residue wassolidified in ethyl acetate to give the hydrochloride of the titlecompound (0.0871 g).

Hydrochloride

mp 140-147° C.; ¹H-NMR (DMSO-d₆) δ: F 0.61-0.78 (m, 2H), 0.95-1.28 (m,3H), 1.51-1.83 (m, 10H), 2.00-2.11 (m, 2H), 2.39 (s, 3H), 2.82-2.99 (m,2H), 3.10-3.30 (m, 4H), 3.50-3.62 (m, 2H), 3.80 (d, 1H, J=16.6 Hz), 4.50(d, 1H, J=16.6 Hz), 4.77-4.86 (m, 1H), 5.52 (d, 1H, J=3.4 Hz), 6.31 (dd,1H, J=1.5 Hz, 3.4 Hz), 7.18 (d, 2H, J=8.3 Hz), 7.31 (d, 2H, J=8.3 Hz),7.33-7.44 (m, 4H), 7.62 (d, 1H, J=1.5 Hz); IR (KBr) cm⁻¹: 3430, 2923,1732, 1634, 1470, 1450, 1403, 1190, 1028, 758; MS (ESI) m/z: 586 (MH⁺).

EXAMPLE 3F-2N-[2-[3-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]-propyl]phenyl]-N-(3-cyclohexylpropionyl)aminoaceticacid

The title compound was synthesized from the compound obtained in Example5C-2 in the same manner as in Example 3F-1.

Hydrochloride

mp 125-130° C.; ¹H-NMR (DMSO-d₆) δ: 0.64-0.79 (m, 2H), 0.98-1.19 (m,4H), 1.22-1.40 (m, 2H), 1.40-1.49 (m, 2H), 1.50-1.61 (m, 3H), 1.65-1.98(m, 6H), 1.99-2.0 (m, 2H), 2.38 (s, 3H), 2.45-2.68 (m, 2H), 2.98-3.18(m, 4H), 3.40-3.55 (m, 2H), 3.72 (d, 1H, J=17.1 Hz), 4.50 (d, 1H, J=17.1Hz), 4.74-4.84 (m, 1H), 5.58 (d, 1H, J=3.4 Hz), 6.29 (dd, 1H, J=1.5 Hz,3.4 Hz), 7.14 (d, 2H, J=8.3 Hz), 7.28 (d, 2H, J=8.3 Hz), 7.29-7.44 (m,4H), 7.57 (d, 1H, J=1.5 Hz); IR (KBr) cm⁻¹: 3432, 2923, 2850, 1734,1639, 1470, 1451, 1405, 1187, 1025, 757; MS (ESI) m/z: 614 (MH⁺).

EXAMPLE 3F-3[2-[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]acetamido]aceticacid

The title compound was synthesized from the compound obtained in Example4B-2 in the same manner as in Example 3F-1.

Hydrochloride

mp 216-219° C.; ¹H-NMR (DMSO-d₆) δ: 1.27-1.51 (m, 10H), 1.62-1.80 (m,4H), 1.98-2.06 (m, 2H), 2.09 (s, 2H), 2.38 (s, 3H), 3.00-3.17 (m, 4H),3.45-3.58 (m, 2H), 3.70-3.75 (m, 2H), 4.73-4.83 (m, 1H), 5.50 (d, 1H,J=3.4 Hz), 6.31 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.15 (d, 2H, J=8.3 Hz), 7.30(d, 2H, J=8.3 Hz), 7.62 (d, 1H, J=1.5 Hz), 8.18 (t, 1H, J=5.9 Hz); IR(KBr) cm⁻¹: 3427, 2927, 2859, 1737, 1640, 1557, 1512, 1469, 1402, 1343,1189, 1032, 758; MS (ESI) m/z: 510 (MH⁺).

EXAMPLE 3F-42-[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]acetyliminodiaceticacid

The title compound was synthesized from the compound obtained in Example4B-1 in the same manner as in Example 3F-1.

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.26-1.51 (m, 10H), 1.61-1.77 (m, 2H), 1.78-1.88 (m,2H), 1.99-2.08 (m, 2H), 2.19 (s, 2H), 2.39 (s, 3H), 2.90-2.99 (m, 2H),3.01-3.16 (m, 2H), 3.42-3.54 (m, 2H), 3.95 (s, 2H), 4.20 (s, 2H),4.74-4.87 (m, 1H), 5.51 (d, 1H, J=3.4 Hz), 6.31 (dd, 1H, J=1.5 Hz, 3.4Hz), 7.15 (d, 2H, J=8.3 Hz), 7.30 (d, 2H, J=8.3 Hz), 7.62 (d, 1H, J=1.5Hz).

EXAMPLE 3F-5N-[1-[2-[1-(2-Aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

tert-Butyl[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]ethyl]carbamate(0.4760 g) was dissolved in a 4N hydrochloric acid/1,4-dioxane solution(10.0 mL) and methanol (5 mL). The solution was stirred at roomtemperature for 2 hours. The solvent was distilled off under reducedpressure to give the title compound (0.5036 g).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.28-1.30 (m, 4H), 1.31-1.50 (m, 6H), 1.52-1.68 (m,4H), 1.83-2.08 (m, 2H), 2.09-2.18 (m, 2H), 2.37 (s, 3H), 2.70-2.82 (m,2H), 3.00-3.16 (m, 4H), 3.53-3.62 (m, 2H), 4.69-4.79 (m, 1H), 5.90 (d,1H, J=3.4 Hz), 6.35 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.24 (d, 1H, J=7.8 Hz),7.55 (d, 1H, J=1.5 Hz), 7.74 (dd, 1H, J=2.0 Hz, 7.8 Hz), 7.90-8.15 (brm,3H), 8.39 (d, 1H, J=2.0 Hz), 9.90-10.15 (brm, 1H); IR (KBr) cm⁻¹: 3424,2927, 2858, 1632, 1557, 1470, 1385, 1320, 1189, 768; MS (ESI) m/z: 439(MH⁺).

EXAMPLE 3G-13-[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]-1,1-propanedicarboxylicacid

To a solution of triethyl3-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]-1,1,1-propanetricarboxylate(200 mg) in 1,4-dioxane (9 mL) and water (3 mL) was added lithiumhydroxide (100 mg). After stirring the solution at room temperature for7 hours, water was added thereto and it was concentrated under reducedpressure. Acetic acid (0.14 mL) was added to the residue, and thesolution was further concentrated under reduced pressure and to dryness.The residue was purified by chromatography (DIAION HP20 manufactured byMitubishi Chemical Corporation, methanol) to give the title compound(150 mg).

Free Form

¹H-NMR (CDCl₃): 1.03-1.66 (m, 18H), 1.72-1.87 (m, 1H), 1.97-2.21 (m,3H), 2.41 (s, 3H), 2.75-3.03 (m, 3H), 3.48-3.69 (m, 2H), 4.79-4.99 (m,1H), 5.88-6.02 (m, 1H), 6.14-6.29 (m, 1H), 6.90-7.02 (m, 1H), 7.48-7.64(m, 1H), 8.30-8.44 (m, 1H).

Hydrochloride

mp 136-139° C.; ¹H-NMR (DMSO-d₆) δ: 1.12-1.29 (m, 6H), 1.30-1.48 (m,6H), 1.53-1.70 (m, 4H), 1.78-1.94 (m, 2H), 1.98-2.09 (m, 2H), 2.37 (s,3H), 2.86-2.97 (m, 2H), 3.02-3.22 (m, 3H), 3.48-3.58 (m, 2H), 4.68-4.80(m, 1H), 5.91 (d, 1H, J=3.6 Hz), 6.36 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.24(d, 1H, J=8.4 Hz), 7.54-7.57 (m, 1H), 7.73 (dd, 1H, J=2.4 Hz, 8.4 Hz),8.38-8.42 (m, 1H), 9.35-9.51 (m, 1H), 12.29-12.85 (m, 2H); IR (KBr)cm⁻¹: 3424, 2928, 1726, 1633, 1469, 1402, 1339, 1229, 1192, 755; MS(ESI) m/z: 526 (MH⁺).

EXAMPLE 3G-2N-[1-[2-[1-(4-Hydroxy-3-hydroxymethylbutyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

To a solution ofN-[1-[2-[1-(4-methoxymethoxy)-3-(methoxymethoxymethyl)butyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide(300 mg) in methanol (10 mL) was added conc. hydrochloric acid (0.17 mL)at room temperature. The solution was stirred at room temperature for 16hours. conc. Hydrochloric acid (0.17 mL) was further added to thesolution, and it was stirred at 50° C. for 6 hours. The solution wasconcentrated under reduced pressure, saturated aqueous sodiumbicarbonate solution was added to the residue, and it was extracted withchloroform. The extract was dried over anhydrous sodium sulfate, andthen, concentrated under reduced pressure. The residue was purified bychromatography [silica gel, chloroform-methanol-aqueous ammonia(90:10:0.1)] to give the title compound (260 mg).

Free Form

¹H-NMR (CDCl₃): 1.12-1.30 (m, 9H), 1.31-1.46 (m, 7H), 1.55-1.72 (m, 3H),1.88-1.97 (m, 2H), 2.02-2.13 (m, 2H), 2.19-2.28 (m, 2H), 2.38 (s, 3H),2.93-3.04 (m, 2H), 3.64 (dd, 2H, J=7.2 Hz, 10.8. Hz), 3.78 (dd, 2H,J=3.6 Hz, 10.8 Hz), 4.71 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.94 (d, 1H, J=3.6Hz), 6.19 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.90 (d, 1H, J=8.0 Hz), 7.23 (d,1H, J=1.6 Hz), 7.51 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.38 (d, 1H, J=2.4 Hz).

Hydrochloride

mp 112-115° C.; ¹H-NMR (DMSO-d₆) δ: 1.05-1.46 (m, 15H), 1.51-1.62 (m,2H), 1.76-1.92 (m, 2H), 1.96-2.07 (m, 2H), 2.37 (s, 3H), 2.82-2.97 (m,2h), 3.01-3.17 (m, 2H), 3.27-3.43 (m, 4H), 3.47-3.56 (m, 2H), 4.68-4.80(m, 1H), 5.91 (d, 1H, J=3.2 Hz), 6.35 (dd, 1H, J=2.0 Hz, 3.2 Hz), 7.24(d, 1H, J=8.0 Hz), 7.51-7.58 (m, 1H), 7.73 (dd, 1H, J=2.4 Hz, 8.0 Hz),8.36-8.42 (m, 1H), 9.29-9.46 (m, 1H); IR (KBr) cm⁻¹: 3406, 2928, 1651,1633, 1556, 1470, 1323, 1191, 1032, 768; MS (ESI) m/z: 498 (MH⁺); Anal.Calcd for C₂₉H₄₄ClN₃O₄5/2H₂O: C, 60.14; H, 8.53; N, 7.26. Found: C,60.06; H, 8.36; N, 6.98.

EXAMPLE 3G-3N-[1-[2-[1-[1,3-Dihydroxypropan-2-yl]cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

To a solution ofN-[1-[2-[1-(2-phenyl-1,3-dioxan-5-yl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide(110 mg) in methanol (5 mL) was added 4N hydrochloric acid (0.5 mL).After stirring the solution at room temperature for 2 hours, it wasconcentrated under reduced pressure. Saturated aqueous sodiumbicarbonate solution was added to the residue and it was extracted withchloroform. The combined organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give the titlecompound. To a solution of the residue in ethyl acetate (10 mL) wasadded a 4N hydrochloric acid/ethyl acetate solution (0.15 mL), and thesolution was stirred at room temperature for 1 hour. The crystals thusseparated out were then filtered to give its hydrochloride (60 mg).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.16-1.32 (m, 3H), 1.35-1.49 (m, 8H), 1.67-1.77 (m,2H), 1.77-1.91 (m, 2H), 1.97-2.07 (m, 2H), 2.37 (s, 3H), 2.91-3.02 (m,2H), 3.03-3.16 (m, 2H), 3.42-3.56 (m, 4H), 3.59 (dd, 2H, J=4.0 Hz, 11.2Hz), 4.69-4.79 (m, 1H), 5.92 (d, 1H, J=3.6 Hz), 6.36 (dd, 1H, J=1.6 Hz,3.6 Hz), 7.24 (d, 1H, J=7.6 Hz), 7.54-7.58 (m, 1H), 7.74 (dd, 1H, J=2.4Hz, 7.6 Hz), 8.40 (d, 1H, J=2.4 Hz), 9.07-9.21 (m, 1H); MS (ESI) m/z:470 (MH⁺).

EXAMPLE 3G-4N-[1-[2-[1-[1,3-Dihydroxypropan-2-yl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution ofN-[1-[2-[1-[2,2-dimethyl-1,3-dioxan-5-yl]cyclohexyl]ethyl]-piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(340 mg) in methanol (5 mL) was added 3N hydrochloric acid (1.1 mL) atroom temperature. After stirring the solution for 1 hour, it wasconcentrated under reduced pressure. A solution of the residue inchloroform/diethyl ether was stirred under ice cooling for 1 hour andthe crystals thus separated out was then filtered to give thehydrochloride of the title compound (240 mg). Hydrochloride

m.p. 118-121° C.; ¹H-NMR (DMSO-d₆) δ: 1.14-1.50 (m, 12H), 1.62-1.79 (m,4H), 1.94-2.07 (m, 2H), 2.39 (s, 3H), 2.88-3.03 (m, 2H), 3.04-3.17 (m,2H), 3.40-3.64 (m, 6H), 4.24-4.42 (m, 1H), 4.72-4.86 (m, 1H), 5.44-5.54(m, 1H), 6.25-6.35 (m, 1H), 7.09-7.20 (m, 1H), 7.24-7.34 (m, 1H),7.57-7.67 (m, 1H), 9.24-9.40 (m, 1H); IR (KBr) cm⁻¹: 3396, 2929, 2863,1636, 1604, 1511, 1470, 1402, 1340, 1312, 1189, 1022, 954, 757, 735; MS(ESI) m/z: 469 (MH⁺); Anal. Calcd for C₂₈H₄₁ClN₂O₄.3/7H₂O: C, 66.58; H,8.23; N, 5.46. Found: C, 65.64; H, 8.42; N, 5.32.

EXAMPLE 4A-1 Ethyl4-[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetamido]butyrate

[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]aceticacid (133 mg) and triethylamine (0.04 mL) were suspended inN,N-dimethyl-formamide (10 mL), to which ethyl 4-aminobutyratehydrochloride (69 mg) was added. To the suspension were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78 mg, 0.41mmol) and 1-hydroxybenzotriazole hydrate (63 mg) under ice cooling. Thesolution was stirred at that temperature for 30 minutes. After allowingthe temperature to rise to room temperature, the solution was stirred atthat temperature for 15 hours. Water and saturated aqueous sodiumbicarbonate solution were added to the solution and it was extractedwith chloroform. The organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The resulting residuewas purified by chromatography (NH silica gel, chloroform:methanol=10:1)to give the title compound (142 mg).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.18 (t, 3H, J=7.4 Hz), 1.27-1.42 (m, 10H), 1.64 (tlike, 2H), 1.75-1.91 (m, 5H), 2.01-2.04 (m, 4H), 2.26-2.28 (m, 2H), 2.37(s, 3H), 3.03-3.15 (m, 5H), 3.58 (d, 2H, J=5.8 Hz), 4.04 (q like, 2H),4.77 (t like, 1H), 5.86 (d, 1H, J=3.4 Hz), 6.36 (s, 1H), 7.25 (d, 1H,J=9.8 Hz), 7.59 (s, 1H), 7.74 (d, 1H, J=7.8 Hz), 8.00 (s, 1H), 8.41 (s,1H), 9.55 (m, 1H); IR (KBr) cm⁻¹: 3425, 2928, 2644, 1727, 1644, 1557,1470, 1319, 1188, 1030, 769; MS (ESI) m/z: 567 (MH⁺).

EXAMPLE 4A-2 Ethyl[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetamido]acetate

The title compound was synthesized from the compound obtained in Example3A-3 in the same manner as in Example 4A-1 except that ethylaminoacetate was used instead of ethyl aminobutyrate.

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.16 (t, 3H, J=7.3 Hz), 1.30-1.39 (m, 10H),1.70-1.74 (m, 2H), 1.79-1.85 (m, 2H), 1.97 (d like, 3H), 2.06 (s, 2H),2.35 (s, 3H), 3.05-3.08 (m, 4H), 3.71 (d, 2H, J=5.9 Hz), 4.01 (q, 2H,J=7.3 Hz), 4.71-4.77 (m, 1H), 5.84 (d, 1H, J=3.4 Hz), 6.37 (t, 1H, J=1.9Hz), 7.25 (d, 1H, J=7.8 Hz), 7.59 (s, 1H), 7.74 (d, 1H, J=8.3 Hz), 8.28(t, 1H, J=5.9 Hz), 8.39 (s, 1H), 9.47-9.57 (m, 1H); IR (KBr) cm⁻¹: 3418,3317, 2926, 2855, 1738, 1673, 1635, 1469, 1398, 1343, 1329, 1192, 1177,1164, 757; MS (ESI) m/z: 511 ([M-Et]⁺).

EXAMPLE 4A-3 Ethyl3-[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetamido]propionate

The title compound was synthesized from the compound obtained in Example3A-3 in the same manner as in Example 4A-1 except that ethyl3-aminopropionate was used instead of ethyl 4-aminobutyrate.

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.08 (t, 3H, J=7.3 Hz), 1.27-1.40 (m, 10H),1.71-1.75 (m, 2H), 1.79-1.88 (m, 2H), 1.99-2.04 (m, 4H), 2.37 (s, 3H),2.42-2.44 (m, 2H), 3.06-3.15 (m, 4H), 3.21-3.27 (m, 2H), 3.49-3.52 (m,4H), 4.05 (q like, 2H), 4.77 (t like, 1H), 5.86 (d, 1H, J=3.4 Hz), 6.37(dd, 1H, J=2.0, 3.4 Hz), 7.26 (d, 1H, J=7.8 Hz), 7.59 (s, 1H), 7.74 (dd,1H, J=2.0, 5.8 Hz), 8.07 (m, 1H), 8.40 (d, 1H, J=2.0 Hz), 9.51-9.61 (m,1H); IR (KBr) cm⁻¹: 3440, 2927, 1731, 1651, 1644, 1633, 1557, 1470,1190, 1031; MS (ESI) m/z: 553 (MH⁺).

EXAMPLE 4A-4 Ethyl4-[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclopentyl]acetamido]butyrate

The title compound was synthesized from the compound obtained in Example3A-4 in the same manner as in Example 4A-1.

¹H-NMR (CDCl₃) δ: 1.57 (t, 3H, J=7.3 Hz), 1.30-1.33 (m, 3H), 1.51-1.60(m, 11H), 1.70-1.86 (m, 5H), 2.00 (m, 5H), 2.20-2.35 (m, 7H), 3.00-3.12(m, 8H), 3.46 (d, 1H, J=10.7 Hz), 4.03 (q, 2H, J=6.8, 10.2 Hz), 4.74 (m,1H), 5.83 (d, 1H, J=3.4 Hz), 6.36 (dd, 1H, J=1.9, 3.4 Hz), 7.25 (d, 1H,J=8.3 Hz), 7.59 (d, 1H, J=1.0 Hz), 7.73 (d, 1H, J=1.9H), 8.02 (m, 1H),8.39 (s, 1H); IR (KBr) cm⁻¹: 3426, 2950, 1728, 1643, 1470, 1338, 1190,1030, 755; MS (ESI) m/z: 553 (MH⁺).

EXAMPLE 4B-1 Di-tert-butyl2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]acetyliminodiacetate

[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]aceticacid (0.2144 g) and di-tert-butyl iminodiacetate (0.2389 g) weredissolved in dichloromethane (5 mL). To this were addedN,N-diisopropylethylamine (0.18 g) and then 2-bromo-1-ethylpyridiniumtetrafluoroborate (0.26 g) at room temperature. The solution was stirredfor 20 hours. After addition of ethyl acetate (60 mL), the solution waswashed in turn with saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution. It was dried over (MgSO₄),and the solvent was distilled off under reduced pressure. The resultingresidue was purified by chromatography [silica gel,dichloromethane-methanol-aqueous ammonia (90:3:0.2 to 95:5:0.3)] to givethe title compound (0.2722 g).

¹H-NMR (DMSO-d₆) δ: 1.20-1.50 (m, 12H), 1.38 (s, 9H), 1.42 (s, 9H),1.50-1.60 (m, 2H), 1.68-1.78 (m, 2H), 1.87-2.01 (m, 2H), 2.15 (s, 2H),2.10-2.22 (m, 2H), 2.37 (s, 3H), 2.80-2.93 (m, 2H), 3.86 (s, 2H), 4.07(s, 2H), 4.43-4.54 (m, 1H), 5.47 (d, 1H, J=3.4 Hz), 6.28 (dd, 1H, J=1.5Hz, 3.4 Hz), 7.07 (d, 2H, J=8.3 Hz), 7.25 (d, 2H, J=8.3 Hz), 7.58 (d,1H, J=1.5 Hz).

EXAMPLE 4B-2 tert-Butyl[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]acetamido]acetate

The title compound was synthesized from the compound obtained in Example3B-1 in the same manner as in Example 4B-1. This product was subjectedto the subsequent step without further purification.

EXAMPLE 4B-3 Ethyl4-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetamido]butyrate

The title compound was synthesized from the compound obtained in Example3B-1 in the same manner as in Example 4B-1.

¹H-NMR (DMSO-d₆): 1.18 (t, 3H, J=7.3 Hz), 1.16-1.52 (m, 12H), 1.56-1.64(m, 2H), 1.71-1.82 (m, 2H), 1.90-2.10 (brm, 2H), 1.98 (s, 2H), 2.16-2.34(m, 4H), 2.37 (s, 3H), 2.84-3.02 (m, 4H), 3.10-3.35 (brm, 2H), 4.04 (q,2H, J=7.3 Hz), 4.44-4.56 (m, 1H), 5.47 (d, 1H, J=3.4 Hz), 6.28 (dd, 1H,J=1.5 Hz, 3.4 Hz), 7.09 (d, 2H, J=8.3 Hz), 7.25 (d, 2H, J=8.3 Hz), 7.59(d, 1H, J=1.5 Hz), 7.70-7.76 (m, 1H).

EXAMPLE 4B-4 Tetraethyl2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]acetylimino-N,N-bis(acetyliminodiacetate)

The title compound was synthesized from the compound obtained in Example3B-1 in the same manner as in Example 4B-1.

¹H-NMR (DMSO-d₆) δ: 1.15-1.24 (m, 12H), 1.25-1.39 (brm, 10H), 1.40-1.48(brm, 2H), 1.49-1.61 (m, 2H), 1.66-1.82 (brm, 2H), 1.83-2.00 (brm, 2H),2.07 (s, 2H), 2.07-2.22 (brm, 2H), 2.37 (s, 3H), 2.80-2.95 (brm, 2H),4.04-4.31 (m, 20H), 4.41-4.55 (brm, 1H), 5.46 (d, 1H, J=3.4 Hz), 6.29(dd, 1H, J=2.0 Hz, 3.4 Hz), 7.09 (d, 2H, J=8.3 Hz), 7.26 (d, 2H, J=8.3Hz), 7.59 (d, 1H, J=2.0 Hz); IR (NaCl film) cm⁻¹: 2928, 1744, 1676,1643, 1470, 1405, 1189, 1025, 757, 736; MS (ESI) m/z: 910 (MH⁺).

EXAMPLE 4B-52-Acetoxymethyl-2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetamido-1,3-diacetoxypropane

The title compound was synthesized from the compound obtained in Example3A-3 in the same manner as in Example 4A-1. This product was subjectedto the subsequent step without further purification.

EXAMPLE 4B-6N-[1-[2-[1-[N,N-Bis[N-[tris(acetoxymethyl)methyl]carbamoylmethyl]carbamoylmethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example3A-3 in the same manner as in Example 4A-1. This product was subjectedto the subsequent step without further purification.

EXAMPLE 4C-1 Diethyl2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetyliminodiacetate

[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxa-mido]piperidin-1-yl]ethyl]cyclohexyl]aceticacid (0.2527 g) was dissolved in dichloromethane (5 mL) andN,N-dimethylformamide (5 drops) under ice cooling. Oxalyl chloride (0.10mL) was added to the solution dropwise. The temperature was allowed torise to room temperature, at which the solution was stirred for 1 hour.The solvent was distilled off under reduced pressure, anddichloromethane (3 mL) was added under ice cooling to dissolve theresidue. To this was added a solution of ethyl iminodiacetate (0.21 g)and triethylamine (0.23 g) in dichloromethane (2 mL), which was thenstirred at room temperature for 2 days. The reaction solution withoutany pre-treatment was purified by chromatography [silica gel,dichloromethane-methanol-aqueous ammonia (95:5:0.3)] to give the titlecompound (0.1702 g).

¹H-NMR (DMSO-d₆) δ: 1.17 (t, 3H, J=7.3 Hz), 1.21 (t, 3H, J=7.3 Hz),1.25-1.50 (m, 12H), 1.52-1.59 (m, 2H), 1.70-1.78 (m, 2H), 1.88-1.96 (m,2H), 2.11-2.20 (m, 2H), 2.19 (s, 2H), 2.35 (s, 3H), 2.82-2.89 (m, 2H),3.99 (s, 2H), 4.06 (q, 2H, J=7.3 Hz), 4.13 (q, 2H, J=7.3 Hz), 4.25 (s,2H), 4.42 (tt, 1H, J=3.4 Hz, 12.2 Hz), 5.84 (d, 1H, J=3.4 Hz), 6.32 (dd,1H, J=1.5 Hz, 3.4 Hz), 7.16 (d, 1H, J=8.3 Hz), 7.52 (d, 1H, J=1.5 Hz),7.67 (dd, 1H, J=2.4 Hz, 8.3 Hz), 8.35 (d, 1H, J=2.4 Hz); IR (NaCl, film)cm⁻¹: 2927, 1746, 1650, 1645, 1470, 1189, 1028, 754; MS (ESI) m/z: 625(MH⁺).

EXAMPLE 4D-1N-[1-[2-[1-(Carbamoylmethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxa-mido]piperidin-1-yl]ethyl]cyclohexyl]aceticacid (909 mg), ammonium chloride (216 mg),benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (1.56g), 1-hydroxybenzotriazole hydrate (470 mg) and N,N-diisoprpoylamine(1.4 mL) were dissolved in N,N-dimethylformamide (8 mL). The solutionwas stirred at room temperature for 22 hours. Saturated aqueous sodiumbicarbonate solution was added to the solution, and it was extractedwith chloroform. The organic layer was dried over anhydrous magnesiumsulfate, filtered, and then, the solvent was distilled off under reducedpressure. The resulting residue was purified by chromatography (silicagel, chloroform:methanol=10:1) to give the title compound (652 mg).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.29-1.42 (m, 10H), 1.73-1.87 (m, 4H), 1.99-2.05 (m,4H), 2.37 (s, 3H), 3.06-3.11 (m, 4H), 3.52 (d, 1H, J=12.2 Hz), 4.77 (tlike, 1H), 5.87 (d, 1H, J=3.4 Hz), 6.36 (dd, 1H, J=1.5, 2.9 Hz), 6.85(s, 1H), 7.25 (d, 1H, J=7.8 Hz), 7.38 (s, 1H), 7.59 (s, 1H), 7.75 (d,1H, J=7.8 Hz), 8.40 (s, 1H); IR (KBr) cm⁻¹: 3417, 2927, 1651, 1469,1402, 1338, 1230, 1191, 1031, 754; MS (ESI): m/z 453 (MH⁺).

EXAMPLE 4D-2N-[1-[2-[1-(Cyanomethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

To a solution ofN-[1-[2-[1-(carbamoylmethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide(154 mg) dissolved in dichloromethane (3 mL) was added triethylamine(0.10 mL). Methanesulfonyl chloride (0.038 mL) was added to the solutionunder ice cooling. After allowing the temperature to rise to roomtemperature, the solution was stirred for 24 hours. Triethylamine (0.14mL) and methanesulfonyl chloride (0.063 mL) were further added to thesolution under ice cooling. The solution was stirred at room temperaturefor 24 hours. Water was added to he solution and it was extracted withchloroform. The organic layer was dried over anhydrous magnesiumsulfate, and then, the solvent was distilled off under reduced pressure.The resulting residue was purified by chromatography (silica gel,chloroform:methanol=20:1) to give the title compound (133 mg).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.22-1.40 (m, 10H), 1.70-1.73 (m, 2H), 1.75-1.88 (m,2H), 2.01 (d, 1H, J=13.7 Hz), 2.35 (s, 3H), 2.54 (s., 2H), 2.97 (m, 2H),3.09 (q like, 2H), 4.75 (t like, 1H), 5.84 (d, 1H, J=3.4 Hz), 6.36 (dd,1H, J=1.9, 3.9 Hz), 7.25 (d, 1H, J=8.3 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.74(dd, 1H, J=2.0, 7.8 Hz), 8.39 (d, 1H, J=7.8 Hz), 9.87 (m, 1H); IR (KBr)cm⁻¹: 3426, 2927, 2855, 2639, 2239, 1643, 1470, 1401, 1336, 1190, 1031,754; MS (ESI) m/z: 435 (MH⁺).

EXAMPLE 4D-3 tert-Butyl[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetohydroxamate

[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]aceticacid (366 mg), O-(tert-butyl)hydroxylamine hydrochloride (304 mg),1-hydroxybenzotriazole hydrate (187 mg) and triethylamine (0.56 mg) weredissolved in dichloromethane (15 mL). To this was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (239 mg)under cooling and the solution was stirred for 1 hour. The temperaturewas gradually allowed to rise to room temperature, and the solution wasstirred for 44 hours. The solvent was distilled off under reducedpressure. The resulting residue was purified by chromatography (silicagel, chloroform:methanol=95:5) to give the title compound (390 mg).

Free Form

¹H-NMR (DMSO-d₆) δ: 1.11 (s, 9H), 1.24-1.27 (m, 3H), 1.35-1.65 (m, 12H),1.96 (d, 2H, J=12.7 Hz), 2.07 (s, 2H), 2.13-2.18 (m, 2H), 2.32-2.35 (m,2H), 2.39 (s, 3H), 3.06 (d, 1H, J=11.3 Hz), 4.72 (tt, 1H, J=3.9, 7.8,12.2 Hz), 5.93 (d, 1H, J=3.4 Hz), 6.19 (dd, 1H, J=1.9, 3.4 Hz), 6.99 (d,1H, J=7.8 Hz), 7.22 (d, 1H, J=0.9 Hz), 7.52 (dd, 1H, J=2.5, 7.8 Hz),8.38 (d, 1H, J=2.0 Hz), 9.60 (m, 1H); IR (KBr) cm⁻¹: 3443, 3239, 2926,2857, 1651, 1592, 1573, 1470, 1365, 1329, 1249, 1233, 1189, 1029, 754;MS (ESI) m/z: 525 (MH⁺).

EXAMPLE 4D-4[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetohydroxamicacid

To tert-butyl[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetohydroxamate(266 mg) was added trifluoroacetic acid (3.0 mL), and the solution wasstirred at room temperature for 23 hours. The solution was then stirredat 40° C. for 2 hours and trifluoroacetic acid (2.0 mL) was furtheradded. The solution was stirred at 50° C. for 3 hours. Thetrifluoroacetic acid was distilled off by azeotropic distillation withxylene. Water and chloroform were added to the residue and the solutionwas neutralized with saturated aqueous sodium hydrogencarbonatesolution. The solution was extracted with 20% ethanol/chloroform. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andthen, the solvent was distilled off under reduced pressure. Theresulting residue was purified by chromatography (silica gel,chloroform:methanol=85:15) to give the title compound (75 mg).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.27-1.41 (m, 10H), 1.72-1.85 (m, 4H), 1.91 (s, 2H),2.03 (d, 2H, J=11.2 Hz), 2.37 (s, 3H), 3.06-3.12 (m, 3H), 3.52 (d, 2H,J=12.2 Hz), 4.78 (t like, 1H), 5.87 (d, 1H, J=3.5 Hz), 6.37 (dd, 1H,J=1.5, 3.0 Hz), 7.26 (d, 1H, J=7.8 Hz), 7.59 (s, 1H), 7.75 (d, 1H, J=5.3Hz), 8.41 (s, 1H), 8.73 (s, 1H), 9.32 (m, 1H), 10.46 (s, 1H); IR (KBr)cm⁻¹: 3426, 3191, 2928, 1644, 1469, 1400, 1341, 1911, 1034, 755; MS(ESI) m/z: 469 (MH⁺).

EXAMPLE 4D-5 tert-Butyl[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetohydroxamate

The title compound was synthesized from the compound obtained in Example3B-1 in the same manner as in Example 4D-3.

¹H-NMR (CDCl₃) δ: 1.03 (s, 9H), 1.24 (d, 2H, J=11.7 Hz), 1.33-1.50 (m,12H), 1.87 (d, 2H, J=11.7 Hz), 2.06 (s, 2H), 2.15 (t, 2H, J=11.7 Hz),2.31-2.35 (m, 2H), 2.40 (s, 3H), 3.05 (d, 2H, J=11.7 Hz), 4.79 (t, 1H,J=12.2 Hz), 5.34 (s, 1H), 6.14 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.01 (d, 2H,J=8.3 Hz), 7.20 (d, 2H, J=7.9 Hz), 7.35 (d, 1H, J=1.4 Hz), 9.61-9.71 (m,1H).

EXAMPLE 4D-6 tert-Butyl[1]-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetohydroxamate(7288),[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetohydroxamicacid

The title compound was synthesized from the compound obtained in Example4D-5 in the same manner as in Example 4D-4.

¹H-NMR (DMSO-d₆) δ: 1.25-1.39 (m, 10H), 1.65-1.73 (m, 4H), 1.88 (brs,2H), 2.01 (d, 2H, J=13.7 Hz), 2.37 (s, 3H), 3.01-3.06 (m, 2H), 3.08-3.14(m, 2H), 3.39-3.51 (m, 4H), 4.80 (t like, 1H), 5.41 (brs, 1H), 6.33 (dd,1H, J=1.9 Hz, 3.9 Hz), 7.16 (d, 2H, J=7.8 Hz), 7.29 (d, 2H, J=8.3 Hz),7.66 (d, 1H, J=1.0 Hz), 9.40-9.51 (m, 1H), 10.47 (s, 1H).

EXAMPLE 4D-7N-[1-[2-[1-(2-Tetrazolylethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

To a solution ofN-[1-[2-[1-(2-cyanoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide(355 mg) dissolved in toluene (2 mL) were added trimethylsilylazide(0.21 mL) and di-n-butyltin oxide (19.7 mg). The solution was heatedunder reflux for 11 hours. Trimethylsilylazide (0.42 mL) anddi-n-butyltin oxide (98.0 mg) were further added to the solution and itwas heated under reflux for 4 hours. The solvent was distilled off underreduced pressure (by azeotropic distillation with methanol). Theresulting residue was purified by chromatography (silica gel,chloroform:methanol=80:20) to give the title compound (385 mg).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.25-1.42 (m, 10H), 1.60-1.68 (m, 4H), 1.78-1.91 (m,3H), 2.03 (d, 2H, J=8.8 Hz), 2.37 (s, 3H), 2.80 (d, 2H, J=8.7 Hz), 3.01(m, 2H), 3.11-3.15 (m, 2H), 3.59 (d, 2H, J=10.7 Hz), 4.74 (m, 1H), 5.87(d, 1H, J=3.4 Hz), 6.35 (d like, 1H), 7.59 (s, 1H), 7.75 (d like, 1H),8.41 (m, 1H); MS (ESI) m/z: 492 (MH⁺).

EXAMPLE 4D-8N-[1-[2-[1-(2-Tetrazolylethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example2-11 in the same manner as in Example 4D-7.

Hydrochloride

mp 90-92° C.; ¹H-NMR (DMSO-d₆) δ: 1.22-1.51 (m, 10H), 1.59-1.80 (m, 6H),1.98-2.10 (m, 2H), 2.38 (s, 3H), 2.77-2.86 (m, 2H), 2.99-3.08 (m, 2H),3.10-3.22 (m, 2H), 3.52-3.63 (m, 2H), 4.72-4.84 (m, 1H), 5.51 (d, 1H,J=3.4 Hz), 6.31 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.17 (d, 2H, J=8.3 Hz), 7.30(d, 2H, J=8.3 Hz), 7.62 (d, 1H, J=1.5 Hz); IR (KBr) cm⁻¹: 3431, 2926,2855, 1633, 1557, 1512, 1470, 1404, 1044, 757, 735; MS (ESI) m/z: 491(MH⁺).

EXAMPLE 5A-1N-[1-[3-(2-Aminophenyl)propyl]piperidin-4-yl]-N-(5-methyl-pyridin-2-yl)-2-furancarboxamide

To a solution of tert-butyl[2-[3-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperi-din-1-yl]propyl]phenyl]carbamate(790 mg) in methanol (15 mL) was added a 4N hydrochloric acid/ethylacetate solution (2.3 mL) at room temperature. The solution was stirredat room temperature for 16 hours. The solution was then concentratedunder reduced pressure. Saturated aqueous sodium bicarbonate solutionwas added to the residue and the solution was extracted with chloroform.The extract was dried over over anhydrous sodium sulfate, and then,concentrated under reduced pressure to give the title compound (700 mg).

¹H-NMR (CDCl₃) δ: 1.52-1.67 (m, 2H), 1.71-1.83 (m, 2H), 1.90-1.99 (m,2H), 2.04-2.16 (m, 2H), 2.26-2.33 (m, 2H), 2.40 (s, 3H), 2.50 (t, 2H,J=7.2 Hz), 2.90-3.02 (m, 2H), 4.73 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.95 (d,1H, J=3.2 Hz), 6.20 (dd, 1H, J=1.6 Hz, 3.2 Hz), 6.58-6.64 (m, 1H),6.65-6.72 (m, 1H), 6.95-7.03 (m, 3H), 7.19-7.25 (m, 1H), 7.52 (dd, 1H,J=2.4 Hz, 7.6 Hz), 8.38-8.43 (m, 1H).

EXAMPLE 5A-2N-[1-[3-(2-Aminophenyl)ethyl]piperidin-4-yl]-N-(5-methylpyr-idin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example2-37 in the same manner as in Example 5A-1.

¹H-NMR (DMSO-d₆) δ: 1.85-2.01 (m, 2H), 2.02-2.11 (m, 2H), 2.37 (s, 3H),3.08-3.25 (m, 6H), 3.32-3.40 (m, 2H), 3.56-3.67 (m, 2H), 4.72-4.83 (m,1H), 5.91 (d, 1H, J=3.6 Hz), 6.36 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.24-7.43(m, 5H), 7.54-7.59 (m, 1H), 7.75 (dd, 1H, J=2.4 Hz, 8.4 Hz), 8.41 (d,1H, J=2.4 Hz); IR (KBr) cm⁻¹: 3426, 2927, 1624, 1572, 1559, 1469, 1320,1190, 767; MS (ESI) m/z: 405 (MH⁺); Anal. Calcd for C₂₄H₃₁Cl₃N₄O₂1/3H₂O:C, 55.45; H, 6.14; N, 10.78. Found: C, 55.32; H, 6.31; N. 10.55.

EXAMPLE 5A-3N-[1-[3-(2-Aminophenyl)propyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example2-36 in the same manner as in Example 5A-1.

¹H-NMR (CDCl₃) δ: 1.40-1.59 (m, 2H), 1.71-1.82 (m, 2H), 1.83-1.92 (m,2H), 2.05-2.20 (m, 2H), 2.24-2.36 (m, 2H), 2.42 (s, 3H), 2.49 (t, 2H,J=7.2 Hz), 2.89-3.05 (m, 2H), 3.84-4.29 (m, 2H), 4.77 (tt, 1H, J=4.0 Hz,12.0 Hz), 5.29-5.41 (m, 1H), 6.09-6.17 (m, 1H), 6.60 (d, 1H, J=7.2 Hz),6.68 (d, 1H, J=7.2 Hz), 6.97-7.04 (m, 4H), 7.21 (d, 2H, J=8.0 Hz),7.31-7.38 (m, 1H).

EXAMPLE 5B-1N-[1-[3-[2-(3-Cyclohexylpropionamido)phenyl]propyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

To a solution ofN-[1-[3-(2-aminophenyl)propyl]piperidin-4-yl]-N-(5-methyl-pyridin-2-yl)-2-furancarboxamide(100 mg) and cyclohexylpropionic acid (49 mg) in dichloromethane (3 mL)were added 1-hydroxybenzotriazole (42 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg)under ice cooling. The solution was stirred at room temperature for 64hours. Chloroform was then added to the solution and the solution waswashed in turn with water and saturated aqueous sodium bicarbonatesolution. The solution was dried over anhydrous sodium sulfate, andthen, concentrated under reduced pressure. The residue was purified bychromatography (NH silica gel, hexane:ethyl acetate=1:2) to give thetitle compound (120 mg).

Free Form

¹H-NMR (CDCl₃): 0.77-0.93 (m, 2H), 1.08-1.33 (m, 5H), 1.44-1.53 (m, 2H),1.55-1.76 (m, 6H), 1.77-1.86 (m, 2H), 1.90-2.00 (m, 2H), 2.03-2.20 (m,6H), 2.42 (s, 3H), 2.55-2.62 (m, 2H), 2.87-2.98 (m, 2H), 4.66-4.80 (m,1H), 5.96-6.01 (m, 1H), 6.18-6.23 (m, 1H), 6.96-7.02 (m, 1H), 7.03-7.20(m, 3H), 7.21-7.25 (m, 1H), 7.51-7.60 (m, 2H), 8.39-8.45 (m, 1H),9.10-9.15 (m, 1H).

Hydrochloride

mp 99-102° C.; ¹H-NMR (DMSO-d₆) δ: 0.82-0.97 (m, 2H), 1.08-1.31 (m, 4H),1.45-1.55 (m, 2H), 1.56-1.77 (m, 5H), 1.79-1.96 (m, 4H), 1.97-2.07 (m,2H), 2.28-2.41 (m, 2H), 2.36 (s, 3H), 2.54-2.63 (m, 2H), 2.91-3.03 (m,2H), 3.04-3.18 (m, 2H), 3.41-3.52 (m, 2H), 4.70-4.81 (m, 1H), 5.90 (d,1H, J=3.2 Hz), 6.35 (dd, 1H, J=1.6 Hz, 3.2 Hz), 7.10-7.33 (m, 5H),7.53-7.58 (m, 1H), 7.73 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.39 (d, 1H, J=2.4Hz), 9.26 (brs, 1H), 9.38-9.78 (m, 1H); IR (KBr) cm⁻¹: 3425, 2922, 2849,1651, 1520, 1470, 1453, 1322, 1189, 1131, 756; MS (ESI) m/z: 557 (MH⁺);Anal. Calcd for C₃₄H₄₅ClN₄O₃.2H₂O: C, 64.90; H, 7.85; N, 8.90. Found: C,65.07; H, 7.77; N, 8.69.

EXAMPLE 5B-2N-[1-[3-[2-(4-Cyclohexylbutyramido)phenyl]propyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example5A-1 in the same manner as in Example 5B-1.

Free Form

¹H-NMR (CDCl₃): 0.78-0.93 (m, 2H), 1.08-1.29 (m, 6H), 1.52-1.75 (m, 9H),1.77-1.87 (m, 2H), 1.91-2.01 (m, 2H), 2.01-2.18 (m, 6H), 2.42 (s, 3H),2.55-2.63 (m, 2H), 2.90-2.99 (m, 2H), 4.68-4.79 (m, 1H), 5.98 (d, 1H,J=3.6 Hz), 6.21 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.96-7.02 (m, 1H), 7.04-7.20(m, 3H), 7.21-7.25 (m, 1H), 7.51-7.59 (m, 2H), 8.39-8.44 (m, 1H), 9.22(brs, 1H).

Hydrochloride

¹H-NMR (DMSO-d₆,): 0.80-0.94 (m, 2H), 1.06-1.29 (m, 6H), 1.53-1.74 (m,7H), 1.80-1.95 (m, 4H), 1.96-2.06 (m, 2H), 2.25-2.35 (m, 2H), 2.36 (s,3H), 2.55-2.63 (m, 2H), 2.91-3.01 (m, 2H), 3.04-3.17 (m, 2H), 3.41-3.51(m, 2H), 4.75 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.89 (d, 1H, J=3.6 Hz), 6.35(dd, 1H, J=2.0 Hz, 3.6 Hz), 7.09-7.26 (m, 4H), 7.27-7.34 (m, 1H),7.54-7.58 (m, 1H), 7.73 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.36-8.41 (m, 1H),9.27 (brs, 1H), 9.63-9.77 (m, 1H); IR (KBr) cm⁻¹: 3426, 2922, 2848,1642, 1523, 1470, 1449, 1401, 1340, 1190, 1133, 1030, 754; MS (ESI) m/z:571 (MH⁺); Anal. Calcd for C₃₅H₄₇ClN₄O₃ 1/2H₂O: C, 68.22; H, 7.85; N,9.09. Found: C, 68.17; H, 8.11; N, 8.93.

EXAMPLE 5B-3 EthylN-[2-[3-[4-[N-(p-tolyl)-2-furancarboxaimdo]piperidin-1-yl]-propyl]phenyl]-N-(3-cyclohexylpropionyl)aminobutyrate

To a solution of ethylN-[2-[3-[4-[N-(p-tolyl)-2-furancarboxaimdo]piperidin-1-yl]-propyl]phenyl]aminobutyrate(0.2552 g) dissolved in dichloromethane (10 mL) were added3-cyclohexanepropionic acid (0.11 g), N,N-diisopropylethylamine (0.31 g)and 2-bromo-1-ethylpyridinium tetrafluoroborate (0.39 g) successively.The solution was stirred at room temperature for 5 days. After additionof ethyl acetate (50 mL), the solution was washed in turn with saturatedaqueous sodium bicarbonate solution and saturated aqueous sodiumchloride solution, dried over (MgSO₄) and the solvent was distilled offunder reduced pressure. The resulting residue was purified bychromatography [silica gel, dichloromethane-methanol-aqueous ammonia(97:3:0.2)] to give the title compound. This product was subjected tothe subsequent step without further purification.

EXAMPLE 5B-4 Methyl1-[N-[2-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]phenyl]carbamoylmethyl]cyclohexylacetate

To a solution of 1-methoxycarbonylmethylcyclohexylacetic acid (265 mg)in dichloromethane (10 mL) was added N,N-dimethylformamide (one drop)and then oxalyl chloride (0.12 mL) under ice cooling. The solution wasstirred at room temperature for 1 hour and concentrated under reducedpressure. After addition of triethylamine (0.29 mL), a solution of theresidue in dichloromethane (5 mL) was added to a solution ofN-[1-[3-(2-aminophenyl)ethyl]piperidin-4-yl]-N-(5-methylpyr-idin-2-yl)-2-furancarboxamide(250 mg) in dichloromethane (5 mL) under ice cooling. After stirring thesolution under ice cooling for 1 hour, saturated aqueous sodiumbicarbonate solution and chloroform were added to the solution, andthen, it was separated to liquid layers. The organic layer was washed inturn with 1N hydrochloric acid, saturated aqueous sodium bicarbonatesolution and saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresulting residue was purified by chromatography (silica gel,hexane:ethyl acetate=6:4) to give the title compound (320 mg).

Free Form

¹H-NMR (CDCl₃) δ: 1.37-1.59 (m, 8H), 1.60-1.74 (m, 2H), 1.88-2.03 (m,4H), 2.22-2.33 (m, 2H), 2.42 (s, 3H), 2.43 (s, 2H), 2.52-2.63 (m, 4H),2.69-2.78 (m, 2H), 2.95-3.04 (m, 2H), 3.68 (s, 3H), 4.74 (tt, 1H, J=4.0Hz, 12.0 Hz), 5.95 (d, 1H, J=3.6 Hz), 6.20 (dd, 1H, J=1.6 Hz, 3.6 Hz),6.96-7.06 (m, 2H), 7.09-7.14 (m, 1H), 7.14-7.21 (m, 1H), 7.21-7.24 (m,1H), 7.53 (dd, 1H, J=2.4 Hz, 8.0 Hz), 7.82-7.89 (m, 1H), 8.41 (d, 1H,J=2.4 Hz), 9.30 (brs, 1H).

Hydrochloride

mp 104-107° C.; ¹H-NMR (DMSO-d₆): 1.30-1.60 (m, 10H), 1.79-1.98 (m, 2H),2.01-2.13 (m, 2H), 2.37 (s, 3H), 2.54 (s, 2H), 2.58 (s, 2H), 2.89-2.98(m, 2H), 3.13-3.24 (m, 4H), 3.50-3.61 (m, 2H), 3.58 (s, 3H), 4.73-4.84(m, 1H), 5.92 (d, 1H, J=3.6 Hz), 6.36 (dd, 1H, J=1.6 Hz, 3.6 Hz),7.14-7.32 (m, 5H), 7.54-7.59 (m, 1H), 7.74 (dd, 1H, J=2.4 Hz, 8.0 Hz),8.41 (d, 1H, J=2.4 Hz), 9.35-9.40 (m, 1H), 9.50-9.61 (m, 1H); IR (KBr)cm⁻¹: 3426, 2928, 2856, 1727, 1642, 1516, 1469, 1452, 1340, 1191, 755;MS (ESI) m/z: 601 (MH⁺); Anal. Calcd for C₃₅H₄₅ClN₄O₅ 2/3H₂O: C, 64.75;H, 7.19; N, 8.63. Found: C, 64.76; H, 7.38; N, 8.59.

EXAMPLE 5B-5 EthylN-[(1-methoxycarbonylmethylcyclohexyl)acetyl]-N-[2-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]-ethyl]phenyl]aminoacetate

The title compound was synthesized from the compound obtained in Example5D-2 in the same manner as in Example 5B-4.

Free Form

¹H-NMR (CDCl₃) δ: 1.18-1.53 (m, 1H), 1.55-1.70 (m, 2H), 1.90-2.00 (m,2H), 2.14-2.30 (m, 3H), 2.39 (s, 3H), 2.46-2.79 (m, 6H), 2.93-3.05 (m,2H), 3.54-3.59 (m, 1H), 3.57 (s, 3H), 4.15-4.24 (m, 2H), 4.69-4.83 (m,2H), 5.96 (d, 1H, J=3.6 Hz), 6.20 (dd, 1H, J=1.6 Hz, 3.6 Hz), 7.00 (d,1H, J=8.0 Hz), 7.20-7.33 (m, 4H), 7.46 (d, 1H, J=8.0 Hz), 7.52 (dd, 1H,J=2.4 Hz, 8.0 Hz), 8.40 (d, 1H, J=2.4 Hz).

EXAMPLE 5B-6N-[1-[2-[1-[5-Hydroxy-3,3-bis(hydroxymethyl)pentyl]cyclohex-yl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furan-carboxamide

To a solution ofN-[1-[3-(2-aminophenyl)ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide(82 mg) in 1,2-dichloroethane (2 mL) was added cyclohexyl isocyanate (38mg) at room temperature. The solution was stirred at 50° C. for hours.The solution was then concentrated under reduced pressure. The residuewas purified by chromatography (NH silica gel, ethyl acetate) to givethe title compound (70 mg).

Free Form

¹H-NMR (CDCl₃) δ: 1.05-1.19 (m, 3H), 1.20-1.43 (m, 2H), 1.56-1.74 (m,3H), 1.85-2.11 (m, 6H), 2.13-2.26 (m, 2H), 2.40 (s, 3H), 2.54 (t, 2H,J=6.4 Hz), 2.71 (t, 2H, J=6.4 Hz), 2.97-3.09 (m, 2H), 3.60-3.73 (m, 1H),4.51-4.63 (m, 1H), 4.74-4.88 (m, 1H), 6.02 (d, 1H, J=3.6 Hz), 6.21 (dd,1H, J=1.6 Hz, 3.6 Hz), 6.98-7.05 (m, 2H), 7.08-7.13 (m, 1H), 7.15-7.24(m, 2H), 8.20 (brs, 1H), 8.39 (d, 1H, J=2.4 Hz).

Hydrochloride

mp 99-102° C.; ¹H-NMR (DMSO-d₆) δ: 0.82-0.97 (m, 2H), 1.08-1.31 (m, 4H),1.45-1.55 (m, 2H), 1.56-1.77 (m, 5H), 1.79-1.96 (m, 4H), 1.97-2.07 (m,2H), 2.28-2.41 (m, 2H), 2.36 (s, 3H), 2.54-2.63 (m, 2H), 2.91-3.03 (m,2H), 3.04-3.18 (m, 2H), 3.41-3.52 (m, 2H), 4.70-4.81 (m, 1H), 5.90 (d,1H, J=3.2 Hz), 6.35 (dd, 1H, J=1.6 Hz, 3.2 Hz), 7.10-7.33 (m, 5H),7.53-7.58 (m, 1H), 7.73 (dd, 1H, J=2.4 Hz, 8.0 Hz), 8.39 (d, 1H, J=2.4Hz), 9.26 (brs, 1H), 9.38-9.78 (m, 1H); IR (KBr) cm⁻¹: 3425, 2922, 2849,1651, 1520, 1470, 1453, 1322, 1189, 1131, 756; MS (ESI) m/z: 557 (MH⁺);H); Anal. Calcd for C₃₄H₄₅ClN₄O₃.2H₂O: C, 64.90; H, 7.85; N, 8.90.Found: C, 65.07; H, 7.77; N, 8.69.

EXAMPLE 5B-7N-[1-[3-[2-(3-Cyclohexylureido)phenyl]propyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

The title compound was synthesized from the compound obtained in Example5A-1 in the same manner as in Example 5B-6.

Hydrochloride

mp 112-115° C.; ¹H-NMR (DMSO-d₆) δ: 1.05-1.38 (m, 5H), 1.47-1.60 (m,1H), 1.63-1.93 (m, 8H), 1.96-2.07 (m, 2H), 2.38 (s, 3H), 2.58-2.68 (m,2H), 3.00-3.21 (m, 4H), 3.41-3.56 (m, 3H), 4.75-4.89 (m, 1H), 5.49 (d,1H, J=3.6 Hz), 6.31 (dd, 1H, J=1.6 Hz, 3.6 Hz), 6.79-6.86 (m, 1H),6.86-6.93 (m, 1H), 7.05-7.21 (m, 4H), 7.25-7.34 (m, 2H), 7.60-7.65 (m,1H), 7.75-7.82 (m, 1H), 7.83-7.89 (m, 1H), 9.34-9.49 (m, 1H); IR (KBr)cm⁻¹: 3426, 2929, 1694, 1635, 1544, 1471, 1449, 1404, 1339, 1316, 1226,1186, 759; Anal. Calcd for C₃₃H₄₃ClN₄O₃.1/3H₂O: C, 67.73; H, 7.52; N,9.57. Found: C, 67.75; H, 7.67; N, 9.29.

EXAMPLE 5B-8 Ethyl3-[2-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]phenyl]-5-cyclohexylhydantoate

The title compound was synthesized from the compound obtained in Example5D-2 in the same manner as in Example 5B-6.

Free Form

¹H-NMR (CDCl₃) δ: 0.81-1.10 (m, 2H), 1.25 (t, 3H, J=6.8 Hz), 1.28-1.37(m, 2H), 1.47-1.77 (m, 5H), 1.77-1.89 (m, 2H), 1.90-2.02 (m, 2H),2.12-2.25 (m, 2H), 2.40 (s, 3H), 2.45-2.61 (m, 2H), 2.66-2.77 (m, 2H),2.93-3.06 (m, 2H), 3.53-3.69 (m, 2H), 3.91-4.02 (m, 1H), 4.10-4.28 (m,2H), 4.69-4.83 (m, 2H), 5.94 (d, 1H, J=3.6 Hz), 6.20 (dd, 1H, J=1.6 Hz,3.6 Hz), 7.01 (d, 1H, J=8.4 Hz), 7.21-7.33 (m, 4H), 7.49-7.57 (m, 2H),8.40 (d, 1H, J=2.0 Hz); MS (ESI) m/z: 616 (MH⁺).

EXAMPLE 5B-9N-[1-[3-[2-(3-Cyclohexylthioureido)phenyl]propyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution ofN-[1-[3-(2-aminophenyl)propyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(0.42 g) dissolved in 1,2-dichloroethane (5 mL) was added cyclohexylisothiocyanate (0.42 g) at room temperature. The solution was thenheated under reflux for 8 hours. The solution was purified bychromatography [silica gel, dichloromethane-methanol-aqueous ammonia(97:3:0.2-95:5:0.3)] to give the title compound (0.2458 g).

¹H-NMR (DMSO-d₆) δ: 1.09-1.43 (m, 7H), 1.50-1.68 (m, 5H), 1.69-1.77 (m,2H), 1.81-1.89 (m, 2H), 1.90-1.98 (m, 2H), 2.18-2.24 (m, 2H), 2.37 (s,3H), 2.43-2.50 (m, 2H), 2.80-2.89 (m, 2H), 3.98-4.12 (m, 1H), 4.48 (tt,1H, J=3.9 Hz, 12.2 Hz), 5.45 (d, 1H, J=3.4 Hz), 6.28 (dd, 1H, J=1.5 Hz,3.4 Hz), 7.08 (d, 2H, J=8.3 Hz), 7.10-7.20 (m, 5H), 7.25 (d, 2H, J=8.3Hz), 7.59 (d, 1H, J=1.5 Hz), 8.85 (s, 1H); IR (NaCl film) cm⁻¹: 2927,2852, 1636, 1515, 1471, 1327, 1305, 756, 735; MS (ESI) m/z: 559 (MH⁺).

EXAMPLE 5C-1 tert-ButylN-[2-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]phenyl]-N-(cyclohexylacetyl)aminoacetate

N-[1-[2-[2-(Cyclohexylacetamido)phenyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(0.3464 g) and tert-butyl bromoacetate (0.38 g) were dissolved inN,N-dimethylformamide (5 mL). To this was added 60% sodiumhydride/mineral oil (0.0622 g) and the solution was stirred at roomtemperature for 17 hours. After diluting with ethyl acetate (50 mL), thesolution was washed with saturated aqueous sodium chloride solution,dried over (MgSO₄), and the solvent was distilled off under reducedpressure. The resulting residue was purified by chromatography (silicagel, ethyl acetate) to give the title compound (0.1318 g).

¹H-NMR (DMSO-d₆) δ: 0.62-1.88 (m, 17H), 1.40 (s, 9H), 2.02-2.12 (m, 2H),2.37 (s, 3H), 2.44-2.54 (m, 2H), 2.55-2.63 (m, 2H), 2.88-2.96 (m, 2H),3.60 (d, 1H, J=17.1 Hz), 4.45 (d, 1H, J=17.1 Hz), 4.46-4.54 (m, 1H),5.46 (d, 1H, J=3.4 Hz), 6.28 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.09 (d, 2H,J=8.3 Hz), 7.25 (d, 2H, J=8.3 Hz), 7.26-7.48 (m, 4H), 7.59 (d, 1H, J=1.5Hz).

EXAMPLE 5C-2 tert-ButylN-[2-[3-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-propyl]phenyl]-N-(3-cyclohexylpropionyl)aminoacetate

The title compound was synthesized from the compound obtained in Example2-34 in the same manner as in Example 5C-1.

¹H-NMR (DMSO-d₆) δ: 0.60-0.75 (m, 2H), 0.95-1.12 (m, 4H), 1.40 (s, 9H),1.20-1.48 (m, 7H), 1.49-1.69 (m, 4H), 1.70-1.82 (m, 3H), 1.84-2.01 (m,3H), 2.20-2.31 (m, 2H), 2.37 (s, 3H), 2.40-2.52 (m, 2H), 2.79-2.89 (m,2H), 3.60 (d, 1H, J=16.6 Hz), 4.41 (d, 1H, J=16.6 Hz), 4.42-4.53 (m,1H), 5.46 (d, 1H, J=3.4 Hz), 6.28 (dd, 1H, J=2.0 Hz, 3.4 Hz), 7.08 9d,2H, J=8.3 Hz), 7.25 (d, 2H, J=8.3 Hz), 7.21-7.37 (m, 4H), 7.58 (d, 1H,J=2.0 Hz).

EXAMPLE 5D-1 EthylN-[2-[3-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-propyl]phenyl]aminobutyrate

To a solution ofN-[1-[3-(2-aminophenyl)propyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(0.3211 g) dissolved in ethanol (3 mL) were added ethyl 4-bromobutyrate(0.23 g) and then diisopropylamine (0.16 g). The solution was heatedunder reflux for 5 hours. After addition of ethyl acetate (10 mL), thesolution was washed with saturated aqueous sodium chloride solution,dried over (MgSO₄), and the solvent was distilled off under reducedpressure. The resulting residue was purified by chromatography [silicagel, dichloromethane-methanol-aqueous ammonia (97:3:0.2)] to give thetitle compound (0.2552 g).

¹H-NMR (DMSO-d₆) δ: 1.17 (t, 3H, J=7.3 Hz), 1.39-1.42 (m, 2H), 1.56-1.67(m, 2H), 1.70-1.83 (m, 4H), 1.90-2.10 (m, 2H), 2.19-2.33 (m, 4H), 2.37(s, 3H), 2.35-2.43 (m, 2H), 2.83-2.94 (m, 2H), 2.98-3.06 (m, 2H), 4.05(q, 2H, J=7.3 Hz), 4.46-4.58 (m, 1H), 4.86-4.92 (m, 1H), 5.47 (d, 1H,J=3.4 Hz), 6.29 (dd, 1H, J=1.5 Hz, 3.4 Hz), 6.46-6.51 (m, 2H), 6.87-6.90(m, 1H), 6.93-6.98 (m, 1H), 7.10 (d, 2H, J=8.3 Hz), 7.26 (d, 2H, J=8.3Hz), 7.59 (d, 1H, J=1.5 Hz).

EXAMPLE 5D-2 EthylN-[2-[2-[4-[N-(5-methylpyridyl-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]phenyl]aminoacetate

The title compound was synthesized from the compound obtained in Example5A-2 in the same manner as in Example 5D-1.

¹H-NMR (CDCl₃) δ: 1.26 (t, 3H, J=7.2 Hz), 1.58-1.75 (m, 2H), 1.90-2.01(m, 2H), 2.40 (s, 3H), 2.58 (t, 2H, J=6.4 Hz), 2.70 (t, 2H, J=6.4 Hz),3.02-3.13 (m, 2H), 3.79 (s, 2H), 4.18 (q, 2H, J=7.2 Hz), 4.76 (tt, 1H,J=4.0 Hz, 12.0 Hz), 5.98 (d, 1H, J=3.6 Hz), 6.20 (dd, 1H, J=1.6 Hz, 3.6Hz), 6.42 (d, 1H, J=8.0 Hz), 6.63-6.70 (m, 1H), 6.96-7.02 (m, 2H),7.05-7.12 (m, 1H), 7.21-7.25 (m, 1H), 7.51 (dd, 1H, J=2.4 Hz, 8.0 Hz),8.40 (d, 1H, J=2.4 Hz).

EXAMPLE 6N-[1-[2-[1-[2-(N²-Hydroxycarbamidoyl)ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution ofN-[1-[2-[1-(2-cyanoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(synthesized in Example 2-11) (1.75 g) dissolved in ethanol (15 mL) wereadded an aqueous solution (5 mL) of hydroxylamine hydrochloride (0.82 g)and then an aqueous solution (10 mL) of potassium carbonate (1.62 g).The solution was heated to 90° C. for 24 hours. Silica gel (15 g) wasadded to the reaction solution, and then, the solvent was distilled offunder reduced pressure. The resulting residue was purified bychromatography [silica gel, dichloromethane-methanol-aqueous ammonia(0:10:0.5)] to give the title compound (1.4660 g).

Hydrochloride

mp 185-195° C. (dec.); ¹H-NMR (DMSO-d₆) δ: 1.17-1.48 (m, 10H), 1.49-1.66(m, 4H), 1.67-1.81 (m, 2H), 1.98-2.09 (m, 2H), 2.30-2.40 (m, 2H), 2.39(s, 3H), 3.04-3.26 (m, 4H), 3.56-3.68 (m, 2H), 4.71-4.84 (m, 1H), 5.49(d, 1H, J=3.4 Hz), 6.31 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.16 (d, 2H, J=7.8Hz), 7.29 (d, 2H, J=7.8 Hz), 7.62 (d, 1H, J=1.5 Hz); IR (KBr) cm⁻¹:3426, 2929, 2857, 1681, 1620, 1556, 1511, 1469, 1409, 1190, 1034, 757,735; MS (ESI) m/z: 481 (MH⁺).

EXAMPLE 7 Methyl1-[1-hydroxyimino-3-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]propyl]carbamate

N-[1-[2-[1-[2-(N²-Hydroxycarbamidoyl)ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(synthesized in Example 6) (0.4740 g) was dissolved inN,N-dimethylformamide and pyridine (0.12 g). To this was added methylchloroformate (0.092 g) under ice cooling. The solution was stirred atroom temperature for 1 hour. After addition of water, the reactionsolution was extracted with 25% ethanol-chloroform. The extract wasdried over anhydrous magnesium sulfate, and then, the solvent wasdistilled off under reduced pressure. The resulting residue was purifiedby chromatography [silica gel, dichloromethane-methanol-aqueous ammonia(95:5:0.3)] to give the title compound (0.4535 g).

Hydrochloride

mp 150-160° C. (dec.); ¹H-NMR (DMSO-d₆) δ: 1.18-1.52 (m, 12H), 1.54-1.64(m, 2H), 1.65-1.77 (m, 2H), 1.95-2.08 (m, 4H), 2.39 (s, 3H), 2.92-3.02(m, 2H), 3.04-3.19 (m, 2H), 3.50-3.58 (m, 2H), 3.71 (s, 3H), 4.73-4.83(m, 1H), 5.49 (d, 1H, J=3.4 Hz), 6.31 (dd, 1H, J=2.0 Hz, 3.4 Hz), 7.16(d, 2H, J=7.8 Hz), 7.30 (d, 2H, J=7.8 Hz), 7.62 (d, 1H, J=2.0 Hz); IR(KBr) cm⁻¹: 3426, 2928, 2855, 1760, 1644, 1557, 1511, 1469, 1405, 1254,1190, 1033, 952, 885, 757; MS (ESI) m/z: 539 (MH⁺).

EXAMPLE 8N-[1-[2-[1-[2-(2H-5-Thioxo-1,2,4-oxadiazol-3-yl)ethyl]cyclo-hexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution ofN-[1-[2-[1-[2-(N-hydroxycarbamidoyl)ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(synthesized in Example 6) (0.3097 g) dissolved in acetonitrile (10 mL)was added 1,1-thiocarbonyldiimidazole (0.17 g). The orange reactionsolution was changed to a yellow suspension, to which1,8-diazabicyclo[5.4.0]-7-undecene (0.39 g) was added. The solution washeated under reflux for 4 hours. Water was added to the reactionsolution, and it was extracted with 25% ethanol-chloroform. The extractwas dried over anhydrous magnesium sulfate, and then, the solvent wasdistilled off under reduced pressure. The resulting residue was purifiedby chromatography [silica gel, dichloromethane-methanol-aqueous ammonia(90:10:0.5)] to give the title compound (0.2810 g).

Hydrochloride

mp 201-206° C. (dec.); ¹H-NMR (DMSO-d₆): 1.20-1.48 (m, 10H), 1.53-1.77(m, 6H), 2.00-2.09 (m, 2H), 2.38 (s, 3H), 2.48-2.58 (m, 2H), 2.92-3.01(m, 2H), 3.08-3.20 (m, 2H), 3.49-3.61 (m, 2H), 4.73-4.84 (m, 1H), 5.51(d, 1H, J=3.4 Hz), 6.32 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.17 (d, 2H, J=8.3Hz), 7.30 (d, 2H, J=8.3 Hz), 7.62 (d, 1H, J=1.5 Hz); IR (KBr) cm⁻¹:3444, 2925, 2853, 2674, 2644, 1635, 1598, 1470, 1401, 1167, 758; MS(ESI) m/z: 523 (MH⁺).

EXAMPLE 9N-[1-[2-[1-[2-(2H-5-Oxo-1,2,4-oxadiazol-3-yl)ethyl]cyclohex-yl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution of methyl1-[1-hydroxyimino-3-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]propyl]carbamatehydrochloride (synthesized in Example 7) (0.3565 g) dissolved inacetonitrile (10 mL) was added 1,8-diazabicyclo[5.4.0]-7-undecene (0.50g). The solution was heated under reflux for 1 hour. Water (30 mL) wasadded to the reaction solution, and it was extracted with 25%ethanol-chloroform. The extract was dried over anhydrous magnesiumsulfate, and then, the solvent was distilled off under reduced pressure.The resulting residue was purified by chromatography [silica gel,dichloromethane-methanol-aqueous ammonia (90:10:0.5)] to give the titlecompound (0.2818 g).

Hydrochloride

mp 162-168° C. (dec.); ¹H-NMR (DMSO-d₆) δ: 1.19-1.48 (m, 10H), 1.49-1.81(m, 6H), 1.98-2.09 (m, 2H), 2.30-2.48 (m, 2H), 2.39 (s, 3H), 2.90-3.04(m, 2H), 3.05-3.21 (m, 2H), 3.50-3.68 (m, 2H), 4.72-4.84 (m, 1H),5.47-5.53 (m, 1H), 6.29-6.33 (m, 1H), 7.16 (d, 2H, J=8.3 Hz), 7.30 (d,2H, J=8.3 Hz), 7.59-7.63 (m, 1H); IR (KBr) cm⁻¹: 3431, 2927, 2857, 1775,1621, 1602, 1557, 1511, 1470, 1408, 1344, 1190, 1033, 953, 757, 735.

EXAMPLE 10N-[1-[2-[1-(1-Methanesulfonylcarbamoylmethyl)cyclohexyl]eth-yl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]aceticacid (synthesized in Example 3B-1) (203 mg), methanesulfonamide (84 mg),1,3-dicyclohexylcarbodiimide (101 mg) and 4-dimethylaminopyridine (59mg) were dissolved in dichloromethane (5 mL). The solution was stirredat room temperature for 4 days. The reaction solution was concentratedunder reduced pressure. The resulting residue was purified bychromatography [silica gel, dichloromethane-methanol (10:1)] to give thetitle compound (233 mg).

Free Form

¹H-NMR (CDCl₃): 1.21 (d, 2H, J=10.3 Hz), 1.32-1.62 (m, 10H), 1.68 (dlike, 2H), 1.92-1.99 (m, 4H), 2.17 (s, 2H), 2.41 (s, 3H), 2.62-2.76 (m,2H), 2.99 (s, 3H), 3.21 (d, 2H, J=12.2 Hz), 4.74 (t like, 1H), 5.41 (d,1H, J=3.4 Hz), 6.15 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.05 (d, 2H, J=7.8 Hz),7.22 (d, 2H, J=8.3 Hz), 7.35 (d, 1H, J=0.9 Hz).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.24-1.49 (m, 10H), 1.67-1.84 (m, 4H), 1.97-2.07 (m,2H), 2.23 (s, 2H), 2.39 (s, 3H), 2.99-3.08 (m, 2H), 3.13-3.18 (m, 2H),3.24 (s, 3H), 3.45-3.53 (m, 2H), 4.77-4.87 (m, 1H), 5.42 (s, 1H), 6.31(dd, 1H, J=1.5 Hz, 3.4 Hz), 7.16 (d, 2H, J=7.8 Hz), 7.30 (d, 2H, J=7.8Hz), 7.65 (s, 1H), 9.70-9.98 (m, 1H), 11.71-11.81 (m, 1H).

EXAMPLE 11N-[1-[2-[1-(1,1-Dimethylcarbamoylmethyl)cyclohexyl]ethyl]-piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution of[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]aceticacid (synthesized in Example 3B-1) (678 mg) in dichloromethane (15 mL)was added dropwise N,N-dimethylformamide (2 drops) and then oxalylchloride (0.16 mL) under ice cooling. The solution was stirred under icecooling for 2 hours. A 5 mL-aliquot of the reaction solution was takenand then added dropwise to a 50% aqueous dimethylamine solution underice cooling. The reaction solution was stirred for 48 hours while thetemperature was allowed to rise to room temperature. NH Silica gel wasthen added to the solution and concentrated under reduced pressure. Theresidue was purified by chromatography [NH silica gel, hexane:ethylacetate (1:1)] to give the title compound (164 mg).

Hydrochloride

¹H-NMR (CDCl₃) δ: 1.20-1.80 (m, 12H), 2.00-2.25 (m, 6H), 2.22 (s, 2H),2.41 (s, 3H), 2.92 (s, 3H), 2.88-3.00 (m, 2H), 3.02-3.13 (m, 2H), 3.06(s, 3H), 3.50-3.60 (m, 2H), 4.83-4.93 (m, 1H), 5.30-5.45 (m, 1H),6.14-6.17 (m, 1H), 7.04 (d, 2H, J=7.8 Hz), 7.24 (d, 2H, J=7.8 Hz), 7.38(s, 1H)

EXAMPLE 12N-[1-[2-[1-(2-Morpholin-4-yl-2-oxoethyl)cyclohexyl]ethyl]-piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution of[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]aceticacid (synthesized in Example 3B-1) (200 mg) dissolved in dichloromethane(4 mL) was added N,N-dimethylformamide (1 drop) and then oxalyl chloride(0.050 mL) dropwise under ice cooling. The solution was stirred underice cooling for 1 hour. The reaction solution was concentrated underreduced pressure to give the corresponding acid chloride.

To a solution of morpholine (61 mg) dissolved in dichloromethane (4 mL)was added triethylamine (0.13 mL) dropwise. To this was added a solutionof the acid chloride in dichloromethane (3 mL) dropwise, and it wasstirred for 1 hour. After allowing the temperature to rise to roomtemperature, the solution was stirred for 19 hours. Ethyl acetate wasadded to the solution, and then, it was washed in turn with a 10%aqueous citric acid solution, saturated aqueous sodium bicarbonatesolution and saturated aqueous sodium chloride solution. The organiclayer was dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The aqueous layer was againextracted with chloroform, and the organic layer was dried overanhydrous magnesium sulfate and filtered. The combined organic layer wasthen distilled under reduced pressure. The resulting residue wassubjected to column chromatography [NH silica gel, hexane-ethyl acetate(2:1)] to give the title compound (116 mg).

Free Form

¹H-NMR (CDCl₃) δ: 1.33-1.53 (m, 12H), 1.64-1.68 (m, 2H), 1.85 (brd, 2H,J=11.7 Hz), 2.10 (t, 2H, J=11.7 Hz), 2.25-2.30 (m, 4H), 2.40 (s, 3H),2.97 (brd, 2H, J=10.2 Hz), 3.46-3.48.(m, 2H), 3.54-3.67 (m, 6H),4.73-4.79 (t like, 1H), 5.37 (s, 1H), 6.13 (dd, 1H, J=1.4 Hz, 3.4 Hz),7.01 (d, 2H, J=8.3 Hz), 7.18 (d, 2H, J=8.3 Hz), 7.34 (s, 1H).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.20-1.49 (m, 10H), 1.62-1.75 (m, 2H), 1.79-1.89 (m,2H), 2.02-2.09 (brd, 2H, J=12.7 Hz), 2.23 (s, 2H), 2.39 (s, 3H),2.95-3.01 (m, 2H), 3.06-3.15 (m, 2H), 3.46-3.59 (m, 10H), 4.78-4.90 (m,1H), 5.44 (m, 1H), 6.31 (dd, 1H, J=1.5 Hz, 3.5 Hz), 7.16 (d, 2H, J=7.8Hz), 7.30 (d, 2H, J=7.8 Hz), 7.63 (s, 1H), 9.19-9.32 (m, 1H).

EXAMPLE 132-(Acetoxymethyl)-2-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane

2-(Acetoxymethyl)-2-[2-[1-(formylmethyl)cyclohexyl]-ethyl]-1,4-diacetoxybutane(synthesized in Example 3G-5) (280 mg) and 4-(p-toluidino)piperidineditrifluoroacetate (synthesized in Preparation Example 4-5) (356 mg)were suspended in dichloromethane (15 mL). Triethylamine (0.23 mL) wasadded to the suspension at room temperature to form a homogenoussolution, to which acetic acid (0.048 mL) was then added. The solutionwas stirred for 15 minutes. Sodium triacetoxyborohydride (377 mg) wasadded to the solution under ice cooling and the temperature was allowedto rise to room temperature. The solution was stirred for 16 hours.Saturated aqueous sodium bicarbonate solution was added to the solutionand the solution was extracted with chloroform. The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by chromatography [NH silicagel, 33% ethyl acetate/hexane] to give the title compound (334 mg).

¹H-NMR (CDCl₃) δ: 1.18-1.28 (m, 10H), 1.35-1.48 (m, 10H), 2.02-2.14 (m,13H), 2.23-2.29 (m, 5H), 2.82-2.92 (m, 2H), 3.22-3.31 (m, 1H), 3.96 (s,4H), 4.11-4.16 (m, 3H), 6.52 (d, 2H, J=8.3 Hz), 6.97 (d, 2H, J=8.3 Hz).

EXAMPLE 142-(Acetoxymethyl)-2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxa-mido]piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,4-diacetoxybu-tane

To a solution of2-(acetoxymethyl)-2-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane(synthesized in Example 13) (324 mg) dissolved in dichloromethane (4 mL)was added triethylamine (0.16 mL). 2-Furoyl chloride (0.084 mL) wasadded to the solution under ice cooling, and the temperature was thenallowed to rise to room temperature. The solution was stirred for 17hours. A 10% aqueous citric acid solution was added to the solution andthe solution was extracted with chloroform. The organic layer was driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by chromatography [NH silicagel, hexane-ethyl acetate (1:1)] to give the title compound (356 mg).

¹H-NMR (CDCl₃) δ: 1.14-1.28 (m, 6H), 1.29-1.47 (m, 8H), 1.47-1.59 (m,2H), 1.86 (d, 2H, J=10.3 Hz), 2.04-2.11 (m, 12H), 2.17-2.21 (m, 2H),2.40 (s, 3H), 2.96 (d, 2H, J=11.7 Hz), 3.94 (s, 4H), 4.10-4.20 (m, 2H),4.74-4.79 (t like, 1H), 5.35 (brs, 1H), 6.13 (dd, 1H, J=2.0 Hz, 3.4 Hz),7.01 (d, 2H, J=8.3 Hz), 7.18 (d, 2H, J=7.8 Hz), 7.35 (s, 1H); MS (ESI)m/z: 667 (MH⁺).

EXAMPLE 15N-[1-[2-[1-[5-Hydroxy-3,3-bis(hydroxymethyl)pentyl]cyclohex-yl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution of2-(acetoxymethyl)-2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane(synthesized in Example 14) (313 mg) dissolved in methanol (5 mL) wasadded potassium carbonate (39 mg) at room temperature. The solution wasstirred for 20 hours. The reaction solution was concentrated underreduced pressure. Water was added to the resulting residue and extractedwith a mixed solvent of chloroform-ethanol (80:20). The organic layerwas dried over anhydrous magnesium sulfate, filtered and thenconcentrated under reduced pressure to give the title compound (252 mg).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.05-1.12 (m, 4H), 1.12-1.23 (m, 5H), 1.23-1.39 (m,8H), 1.52-1.59 (m, 2H), 1.63-1.79 (m, 2H), 1.98-2.04 (m, 3H), 2.39 (s,3H), 2.92-3.08 (m, 2H), 3.11-3.21 (m, 2H), 3.22-3.35 (m, 4H), 3.45-3.57(m, 5H), 4.77-4.81 (t like, 1H), 5.40 (brs, 1H), 6.32 (dd, 1H, J=2.0 Hz,3.2 Hz), 7.16 (d, 2H, J=7.8 Hz), 7.30 (d, 2H, J=8.3 Hz), 7.66 (s, 1H),9.77-9.93 (brm, 1H); IR (KBr) cm⁻¹: 3388, 2926, 2860, 1633, 1512, 1470,1403, 1342, 1243, 1189, 1032, 757; MS (ESI) m/z: 541 (MH⁺).

EXAMPLE 16 tert-Butyl2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]ethylcarbamate

To a solution of 4-(p-toluidino)piperidine (synthesized in PreparationExample 4-5), N-[2-[1-(formylmethyl)cyclohexyl]ethyl]phthalimide(synthesized in Preparation Example 3K-2) (0.77 g) and acetic acid (0.30mL) in 1,2-dichloroethane (10 mL) was added sodium triacetoxyborohydride(0.82 g). The solution was stirred at room temperature for 1.5 hours.Saturated aqueous sodium bicarbonate solution was added to the solutionand it was extracted with a mixed solvent of chloroform-ethanol (10:1).The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified bychromatography [silica gel, chloroform-methanol (20:1)] to give acolorless oily substance (1.32 g).

¹H-NMR (CDCl₃): 1.35-1.63 (m, 16H), 2.05-2.08 (m, 2H), 2.15-2.23 (m,2H), 2.23 (s, 3H), 2.42-2.46 (m, 2H), 2.94-2.98 (m, 2H), 3.25-3.30 (m,1H), 3.64-3.68 (m, 2H), 6.53 (d, 2H, J=8.3 Hz), 6.97 (d, 2H, J=7.8 Hz),7.69-7.72 (m, 2H), 7.81-7.86 (m, 2H).

To a solution of the resulting oily substance (1.32 g) in ethanol (20mL) was added hydrazine monohydrate (0.37 mL). The solution was heatedunder reflux for 1 hour. The reaction solution was concentrated underreduced pressure (by azeotropic distillation with toluene).Dichloromethane (20 mL), triethylamine (1.0 mL) and di-tert-butyldicarbonate (1.00 g) were successively added to the resulting residue.The solution was stirred at room temperature for 13 hours. The reactionsolution was filtered with Celite and the filtrate was concentratedunder reduced pressure. The residue was purified by chromatography[silica gel, chloroform-methanol (100:1)] to give the title compound(1.08 g).

¹H-NMR (CDCl₃) δ: 1.22-1.51 (m, 16H), 1.44 (s, 9H), 2.03-2.15 (m, 4H),2.23 (s, 3H), 2.28-2.33 (m, 2H), 2.87-2.90 (m, 2H), 3.06-3.10 (m, 2H),3.24-3.28 (m, 1H), 4.62 (br, 1H), 6.52 (d, 2H, J=8.3 Hz), 6.97 (d, 2H,J=7.8 Hz).

EXAMPLE 17 tert-Butyl2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]ethylcarbamate

To a solution of tert-butyl2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]eth-ylcarbamate(synthesized in Example 16) (1.08 g) in dichloromethane (5 mL) wereadded triethylamine (0.68 mL) and then 2-furoyl chloride (0.31 mL). Thesolution was stirred at room temperature for 1 hour. NH Silica gel wasadded to the reaction solution and the solvent was distilled off underreduced pressure. The resulting residue was purified by chromatography[NH silica gel, hexane-ethyl acetate (4:1)] to give the title compound(1.14 g).

¹H-NMR (CDCl₃) δ: 1.24-1.59 (m, 16H), 1.43 (s, 9H), 1.83-1.86 (m, 2H),2.04-2.13 (m, 2H), 2.22-2.26 (m, 2H), 2.39 (s, 3H), 2.95-3.05 (m, 4H),4.50 (br, 1H), 4.72-4.80 (m, 1H), 5.37 (s, 1H), 6.13 (dd, 1H, J=1.5 Hz,3.4 Hz), 7.01 (d, 2H, J=7.8 Hz), 7.18 (d, 2H, J=7.8 Hz), 7.34 (s, 1H).

EXAMPLE 18N-[1-[2-[1-(2-Aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution of tert-butyl2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]ethylcarbamate(synthesized in Example 17) (1.14 g) in methanol (4 mL) was added a 4Nhydrochloric acid/dioxane solution (3 mL). The solution was stirred atroom temperature for 12 hours. The reaction solution was concentratedunder reduced pressure. The resulting residue was purified bychromatography [NH silica gel, chloroform-methanol (20:1)] to give thetitle compound (1.01 g).

Free Form

¹H-NMR (CDCl₃) δ: 1.23-1.57 (m, 16H), 1.83-1.86 (m, 2H), 2.04-2.12 (m,2H), 2.22-2.27 (m, 2H), 2.39 (s, 3H), 2.59-2.64 (m, 2H), 2.94-2.98 (m,2H), 4.72-4.81 (m, 1H), 5.37 (s, 1H), 6.13 (dd, 1H, J=2.0 Hz, 3.4 Hz),7.01 (d, 2H, J=7.8 Hz), 7.17 (d, 2H, J=7.8 Hz), 7.34 (d, 1H, J=2.0 Hz).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.18-1.73 (m, 16H), 2.02-2.05 (m, 2H), 2.39 (s, 3H),2.67-2.78 (m, 2H), 3.00-3.16 (m, 4H), 3.56-3.59 (m, 2H), 4.76-4.83 (m,1H), 5.42 (s, 1H), 6.33 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.17 (d, 2H, J=7.8Hz), 7.31 (d, 2H, J=8.3 Hz), 7.66 (s, 1H), 7.95 (br, 2H), 9.69 (br, 1H);MS (ESI) m/z: 438 (MH⁺).

EXAMPLE 19N-[1-[2-[1-(2-Methanesulfonylaminoethyl)cyclohexyl]ethyl]-piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution ofN-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(synthesized in Example 18) (260 mg) in dichloromethane (3 mL) wereadded triethylamine (0.15 mL) and methanesulfonyl chloride (56 L)successively. The solution was stirred at room temperature for 6 hours.The reaction solution was filtered and the filtrate was concentratedunder reduced pressure. The resulting residue was purified bychromatography [NH silica gel, hexane-ethyl acetate (7:3 to 1:1 to 1:2]to give the title compound (214 mg).

Free Form

¹H-NMR (CDCl₃) δ: 1.22-1.27 (m, 4H), 1.34-1.43 (m, 8H), 1.51-1.60 (m,4H), 1.83-1.87 (m, 2H), 2.08-2.14 (m, 2H), 2.21-2.26 (m, 2H), 2.39 (s,3H), 2.81 (s, 3H), 2.85-2.99 (m, 2H), 3.03-3.08 (m, 2H), 4.71-4.79 (m,1H), 5.37 (s, 1H), 6.13 (dd, 1H, J=1.5 Hz, 3.9 Hz), 7.02 (d, 2H, J=8.3Hz), 7.19 (d, 2H, J=8.3 Hz), 7.34 (s, 1H).

Hydrochloride

mp 235-238° C.; ¹H-NMR (DMSO-d₆) δ: 1.24-1.44 (m, 12H), 1.58-1.73 (m,4H), 1.98-2.05 (m, 2H), 2.39 (s, 3H), 2.85-2.97 (m, 4H), 2.90 (s, 3H),3.07-3.16 (m, 2H), 3.51-3.54 (m, 2H), 4.76-4.85 (m, 1H), 5.43 (s, 1H),6.32-6.33 (m, 1H), 6.91 (t, 1H, J=5.6 Hz), 7.17 (d, 2H, J=7.8 Hz), 7.31(d, 2H, J=7.8 Hz), 7.66 (s, 1H), 9.54 (br, 1H); IR (KBr) cm⁻¹: 3445,3113, 2931, 2858, 2641, 1642, 1557, 1511, 1471, 1398, 1313, 1187, 1153,772, 523; MS (ESI) m/z: 516 (MH⁺).

EXAMPLE 20N-[1-[2-[1-[2-(p-Toluenesulfonylamino)ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution ofN-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(synthesized in Example 18) (228 mg) in dichloromethane (3 mL) wereadded 1,4-diazabicyclo[2.2.2]octane (108 mg) and p-toluenesulfonylchloride (120 mg) successively. The solution was stirred at roomtemperature for 6 hours. The reaction solution was filtered and thefiltrate was concentrated under reduced pressure. The resulting residuewas purified by chromatography [NH silica gel, hexane-ethyl acetate (7:3to 1:2)] to give the title compound (265 mg).

Free Form

¹H-NMR (CDCl₃) δ: 1.16-1.44 (m, 14H), 1.51-1.62 (m, 2H), 1.81-1.85 (m,2H), 1.99-2.05 (m, 2H), 2.10-2.14 (m, 2H), 2.37 (s, 3H), 2.43 (s, 3H),2.83-2.92 (m, 4H), 4.70-4.79 (m, 1H), 5.37 (s, 1H), 6.14 (dd, 1H, J=1.5Hz, 3.4 Hz), 7.03 (d, 2H, J=8.3 Hz), 7.18 (d, 2H, J=8.3 Hz), 7.26 (d,2H, J=6.8 Hz), 7.35 (d, 1H, J=1.5 Hz), 7.62 (d, 2H, J=8.3 Hz).

Hydrochloride

mp 230-235° C.; ¹H-NMR (DMSO-d₆) δ: 1.09-1.39 (m, 12H), 1.48-1.56 (m,2H), 1.63-1.72 (m, 2H), 1.98-2.03 (m, 2H), 2.39 (s, 3H), 2.57-2.72 (m,2H), 2.83-2.90 (m, 2H), 3.04-3.11 (m, 2H), 3.46-3.49 (m, 2H), 4.76-4.83(m, 1H), 5.43 (s, 1H), 6.33 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.17 (d, 2H,J=8.3 Hz), 7.31 (d, 2H, J=8.3 Hz), 7.39 (d, 2H, J=7.8 Hz), 7.51 (t, 1H,J=5.1 Hz), 7.65 (s, 1H), 7.69 (d, 2H, J=8.3 Hz), 9.57 (br, 1H); IR (KBr)cm⁻¹: 3443, 3142, 2928, 2855, 2633, 2534, 1638, 1510, 1473, 1448, 1408,1325, 1188, 1158, 1091, 1057, 807, 766, 726, 616; MS (ESI) m/z: 592(MH⁺).

EXAMPLE 21N-[1-[2-[1-[2-(4-Chlorobenzenesulfonylamino)ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution ofN-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(synthesized in Example 18) (199 mg) in dichloromethane (3 mL) wereadded 1,4-diazabicyclo[2.2.2]octane (100 mg) and p-chlorobenzenesulfonylchloride (100 mg) successively. The solution was stirred at roomtemperature for 2 hours. The reaction solution was diluted withchloroform, washed in turn with saturated aqueous sodium bicarbonatesolution and saturated aqueous sodium chloride solution, and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure. The resulting residue was purified by chromatography [NHsilica gel, hexane-ethyl:acetate (7:3)] to give the title compound (181mg).

Free Form

¹H-NMR (CDCl₃) δ: 1.11-1.64 (m, 16H), 1.83-1.87 (m, 2H), 2.04-2.18 (m,4H), 2.37 (s, 3H), 2.87 (t, 2H, J=6.8 Hz), 2.91-2.95 (m, 2H), 4.72-4.80(m, 1H), 5.37 (s, 1H), 6.14 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.05 (d, 2H,J=8.3 Hz), 7.19 (d, 2H, J=7.8 Hz), 7.34 (s, 1H), 7.40 (d, 2H, J=8.3 Hz),7.60 (d, 2H, J=8.3 Hz).

Hydrochloride

mp 235-241° C.; ¹H-NMR (DMSO-d₆) δ: 1.10-1.40 (m, 12H), 1.52-1.55 (m,2H), 1.61-1.71 (m, 2H), 2.00-2.04 (m, 2H), 2.39 (s, 3H), 2.69-2.75 (m,2H), 2.83-2.92 (m, 2H), 3.04-3.12 (m, 2H), 3.47-3.50 (m, 2H), 4.77-4.83(m, 1H), 5.43 (s, 1H), 6.33 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.17 (d, 2H,J=8.3 Hz), 7.31 (d, 2H, J=7.8 Hz), 7.66 (s, 1H), 7.67 (d, 2H, J=8.3 Hz),7.73 (t, 1H, J=5.4 Hz), 7.82 (d, 2H, J=8.3 Hz), 9.45 (br, 1H); IR (KBr)cm⁻¹: 3450, 3131, 2927, 2855, 2634, 2543, 1638, 1474, 1335, 1161, 1092,1083, 758, 615, 563; MS (ESI) m/z: 612 (MH⁺).

EXAMPLE 222-[2-[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetylamino]benzoicacid

To a solution of[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]aceticacid (synthesized in Preparation Example 3B-1) (678 mg) indichloromethane (15 mL) was added N,N-dimethylformamide (2 drops)dropwise. Oxalyl chloride (228 mg) was then added to the solution underice cooling. The solution was stirred under ice cooling for 2 hours. A5-mL aliquot of the reaction solution was taken and was added to asolution of methyl anthranilate (99 mg) and triethylamine (182 mg) indichloromethane (15 mL) dropwise under ice cooling. The reactionsolution was stirred for 18 hours while the temperature was allowed torise to room temperature. NH Silica gel was then added to the reactionsolution, and it was concentrated under reduced pressure. The residuewas purified by chromatography [silica gel, chloroform-methanol (20:1)]to give methyl2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetylamino]benzoate(150 mg).

To a solution of this product in methanol (5 mL) was added an aqueoussodium hydroxide (51 mg) solution (3 mL) dropwise at room temperature.The solution was stirred at room temperature for 18 hours. Afterneutralizing the solution with 2N hydrochloric acid, silica gel wasadded thereto and it was concentrated under reduced pressure. Theresulting residue was purified by chromatography [silica gel,chloroform-methanol (10:1)] to give the title compound (148 mg).

Free Form

¹H-NMR (CDCl₃) δ: 1.25-1.55 (m, 10H), 1.82-1.90 (m, 2H), 1.93-2.05 (m,4H), 2.21 (s, 2H), 2.32 (s, 3H), 2.76-2.88 (m, 2H), 3.08-3.16 (m, 2H),3.52-3.60 (m, 2H), 4.85-4.96 (m, 1H), 5.32-5.37 (m, 1H), 6.12-6.15 (m,1H), 6.95 (d, 2H, J=8.3 Hz), 6.97-7.03 (m, 1H), 7.09 (d, 2H, J=8.3 Hz),7.33-7.39 (m, 2H), 7.82 (brd, 1H, J=7.8 Hz), 8.54 (brd, 1H, J=8.3 Hz),12.68 (brs, 1H).

Hydrochloride

¹H-NMR (CDCl₃): 1.25-1.55 (m, 10H), 1.93-2.10 (m, 4H), 2.11-2.26 (m,2H), 2.34 (s, 2H), 3.05 (s, 3H), 3.00-3.14 (m, 2H), 3.16-3.26 (m, 2H),3.50-3.60 (m, 2H), 4.88-4.98 (m, 1H), 5.32-5.36 (m, 1H), 6.18 (dd, 1H,J=1.5 Hz, 3.5 Hz), 7.03 (d, 2H, J=8.3 Hz), 7.09-7.15 (m, 1H), 7.24 (d,2H, J=8.3 Hz), 7.38-7.41 (m, 1H), 7.51-7.57 (m, 1H), 8.09-8.12 (m, 1H),8.57-8.60 (m, 1H), 11.10 (brs, 1H).

EXAMPLE 23N-[1-[2-[1-[1-(pirazin-2-yl)carbamoylmethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution of[1-[2-[4-[N-(p-tolyl)-2-furan-carboxamido]piperidin-1-yl]ethyl]cyclohexyl]aceticacid (synthesized in Example 3B-1) (201 mg) dissolved in dichloromethane(6 mL) was added N,N-dimethylformamide (2 drops). Oxalyl chloride (0.060mL) was then added to the solution dropwise under ice cooling. Thesolution was stirred for 1.5 hours. After addition of triethylamine(0.12 mL) at that temperature, the solution was stirred for 20 minutes.2-Aminopyrazine (128 mg) was then added to the solution and it wasstirred at that temperature. The temperature was allowed to rise to roomtemperature and the solution was stirred for 16 hours. NH Silica gel wasadded to the reaction solution, and it was concentrated under reducedpressure. The resulting residue was purified by chromatography [at thefirst stage; NH silica gel, hexane-ethyl:acetate (2:1) and at the secondstage; silica gel, chloroform-methanol (10:1)] to give the titlecompound (116 mg).

Free Form

¹H-NMR (CDCl₃) δ 1.28-1.65 (m, 10H), 1.71-1.84 (m, 6H), 2.27-2.40 (m,9H), 3.10 (brd, 2H, J=11.7 Hz), 4.75-4.81 (t like, 1H), 5.31 (s, 1H),6.12 (d, 1H, J=1.9 Hz), 6.94 (d, 2H, J=8.3 Hz), 7.06 (d, 2H, J=7.9 Hz),7.33 (s, 1H), 7.87 (s, 1H), 8.21 (d, 1H, J=2.4 Hz), 9.38 (s, 1H), 10.27(brs, 1H).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.35-1.56 (m, 12H), 1.67-1.76 (m, 2H), 1.82-1.91 (m,2H), 2.02 (d, 2H, J=16.1 Hz), 2.38-2.41 (m, 5H), 3.11-3.17 (m, 4H), 3.18(s, 2H), 4.79-4.86 (m, 1H), 5.43 (s, 1H), 6.32 (s, 1H), 7.16 (d, 2H,J=8.3 Hz), 7.31 (d, 2H, J=7.8 Hz), 7.65 (s, 1H), 8.34 (s, 1H), 8.39 (s,1H), 9.34 (s, 1H), 9.54-9.66 (m, 1H), 10.77 (s, 1H).

EXAMPLE 24 Dimethyl5-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyelohexyl]ethoxy]isophthalate

2-[1-[2-(tert-Butyldiphenylsiloxy)ethyl]cyclohexyl]-ethanol (synthesizedin Preparation Example 3A-2) (2.03 g) and dimethyl 5-hydroxyisophthalate(1.26 g) were dissolved in benzene (50 mL). To this was addedtriphenylphosphine (1.56 g). Diethyl azocarboxylate (0.95 mL) wasfurther added to the solution at room temperature dropwise. The solutionwas stirred for 3 hours. The reaction solution was concentrated underreduced pressure. The resulting residue was purified by chromatography[silica gel, hexane-ethyl acetate (4:1)] to give the title compound(1.84 g).

¹H-NMR (CDCl₃) δ: 1.02 (s, 9H), 1.31-1.45 (m, 10H), 1.65 (t, 2H, J=7.3Hz), 1.77 (t, 2H, J=7.3 Hz), 3.74 (t, 2H, J=7.3 Hz), 3.96 (t, 2H, J=7.3Hz), 3.94 (s, 6H), 7.33-7.40 (m, 6H), 7.65-7.69 (m, 6H), 8.27 (d, 1H,J=1.5 Hz).

EXAMPLE 25 Dimethyl5-[2-[1-(2-hydroxyethyl)cyclohexyl]ethoxy]isophthalate

To a solution of dimethyl5-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethoxy]isophthalate(synthesized in Example 24) (0.53 g) dissolved in tetrahydrofuran (6 mL)was added a 1M tetrabutylammonium fluoride/tetrahydrofuran solution(1.32 mL) dropwise at room temperature. The solution was stirred for 3hours. A 10% aqueous citric acid solution was added to the solution andit was extracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate, andfiltered. The filtrate was then concentrated under reduced pressure. Theresulting residue was purified by chromatography [silica gel,hexane-ethyl acetate (1:1)] to give the title compound (255 mg).

¹H-NMR (CDCl₃) δ: 1.38-1.55 (m, 11H), 1.69 (t, 2H, J=7.3 Hz), 1.86 (t,2H, J=7.3 Hz), 3.74-3.80 (m, 2H), 3.94 (s, 6H), 4.12 (t, 2H, J=7.3 Hz),7.74 (d, 2H, J=0.9 Hz), 8.27 (s, 1H).

EXAMPLE 26 Dimethyl 5-[2-[1-(formylmethyl)cyclohexyl]ethoxy]isophthalate

1,1,1-Tris(acetoxy)-1,1-dihydro-1,2-benziodooxol-3(1H)-one (444 mg) wassuspended in dichloromethane (4 mL). Pyridine (196 mg) was added to thesuspension to form a nearly homogenous solution. A solution of dimethyl5-[2-[1-(2-hydroxyethyl)cyclohexyl]ethoxy]isophthalate (synthesized inExample 25) (253 mg) dissolved in dichloromethane (4 mL) was added tothe solution dropwise under ice cooling. The solution was stirred atthat temperature for 1.5 hours. After allowing the temperature to riseto room temperature, diethyl ether (50 mL) was added to the solution andit was washed in turn with a 10% aqueous sodium thiosulfate solution (15mL), 1N hydrochloric acid (20 mL), saturated aqueous sodium bicarbonatesolution (20 mL) and saturated aqueous sodium chloride solution (30 mL).The organic layer was dried over anhydrous magnesium sulfate, andfiltered. The filtrate was concentrated under reduced pressure to givethe title compound (253 mg). This product was subjected to thesubsequent step without further purification.

EXAMPLE 27 Dimethyl5-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]-ethoxy]isophthalate

Dimethyl 5-[2-[1-(formylmethyl)cyclohexyl]ethoxy]isophthalate(synthesized in Example 26) (253 mg) and 4-(p-toluidino)piperidineditrifluoroacetate (synthesized in Preparation Example 4-5) weresuspended in 1,2-dichloroethane (8 mL). Triethylamine (170 mg) was addedto the suspension at room temperature to form a homogenous solution.Acetic acid (51 mg) was added to the solution and it was stirred for 10minutes. After addition of sodium triacetoxyborohydride (371 mg) underice cooling, the solution was allowed to rise to room temperature andstirred for 3 hours. Saturated aqueous sodium bicarbonate solution wasadded to the solution and it was extracted with chloroform. The organiclayer was dried over anhydrous sodium sulfate and filtered. The filtratewas then concentrated under reduced pressure. The resulting residue waspurified by chromatography [NH silica gel, chloroform-methanol (10:1)]to give the title compound (296 mg).

¹H-NMR (CDCl₃) δ: 1.28-1.48 (m, 12H), 1.55-1.59 (m, 2H), 1.81-1.85 (tlike, 2H), 2.05-2.12 (m, 5H), 2.22 (s, 3H), 2.34-2.40 (m, 2H), 2.84-2.95(m, 2H), 3.22-3.31 (m, 1H), 3.94 (s, 6H), 4.06-4.10 (t like, 2H), 6.52(d, 2H, J=8.3 Hz), 6.96 (d, 2H, J=8.3 Hz), 7.74 (s, 2H), 8.27 (s, 1H);MS (ESI) m/z 537 (MH⁺).

EXAMPLE 28 Dimethyl5-[2-[1-[2-[N-[4-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethoxy]isophthalate

To a solution of dimethyl5-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]-ethoxy]isophthalate(synthesized in Example 27) (280 mg) dissolved in dichloromethane (5 mL)was added triethylamine (0.14 mL). After addition of 2-furoyl chloride(0.077 mL) under ice cooling, the temperature of solution was allowed torise to room temperature. The solution was stirred for 15 hours. A 10%aqueous citric acid solution was added to the solution and it wasextracted with chloroform. The organic layer was dried over anhydrousmagnesium sulfate and filtered. The filtrate was then concentrated underreduced pressure. The resulting residue was purified by chromatography[NH silica gel, hexane-ethyl acetate (1:1)] to give the title compound(288 mg).

¹H-NMR (CDCl₃): 1.35-1.56 (m, 14H), 1.79 (t, 2H, J=7.3 Hz), 1.87 (d, 2H,J=11.2 Hz), 2.12 (t, 2H, J=11.2 Hz), 2.33 (t, 2H, J=8.3 Hz), 2.39 (s,3H), 2.99 (d, 2H, J=11.7 Hz), 3.94 (s, 6H), 4.03 (t, 2H, J=7.3 Hz), 4.78(t, 1H, J=12.2 Hz), 5.35 (s, 1H), 6.13 (dd, 1H, J=1.9 Hz, 3.4 Hz), 7.01(d, 2H, J=8.3 Hz), 7.17 (d, 2H, J=8.3 Hz), 7.35 (s, 1H), 7.70 (d, 2H,J=1.0 Hz), 8.26 (s, 1H); MS (ESI) m/z 631 (MH⁺).

EXAMPLE 295-[2-[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethoxy]isophthalicacid

To a solution of dimethyl5-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethoxy]isophthalate(synthesized in Example 28) (255 mg) dissolved in methanol (5 mL) wasadded a 2N aqueous sodium hydroxide solution (2.0 mL). The solution wasstirred at room temperature for 24 hours. The reaction solution wasconcentrated under reduced pressure. Water was then added to thesolution, and it was neutralized with acetic acid (0.23 mL) andextracted with chloroform-ethanol (80:20). The organic layer was driedover anhydrous magnesium sulfate and filtered. The filtrate was thenconcentrated under reduced pressure to give the title compound (243 mg).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.23-1.48 (m, 10H), 1.61-1.75 (m, 6H), 1.99-2.01(brd, 2H, J=12.7 Hz), 2.36 (s, 3H), 2.91-2.98 (m, 2H), 3.04-3.19 (m,3H), 4.72-4.83 (t like, 1H), 5.40 (s, 1H), 6.31 (d, 1H, J=2.0 Hz), 7.15(d, 2H, J=7.8 Hz), 7.28 (d, 2H, J=8.3 Hz), 7.63-7.64 (d like, 3H), 8.06(s, 1H); IR (KBr) cm⁻¹: 3426, 2928, 1713, 1621, 1596, 1469, 1469, 1403,1298, 1231, 1192, 1119, 1041, 760; MS (ESI) m/z: 603 (MH⁺).

EXAMPLE 301-[2-[1-[2-(tert-Butyldiphenylsiloxy)ethyl]cyclohexyl]ethoxy]-3,5-dihydroxymethylbenzene

Lithium aluminum hydride (172 mg) was suspended in tetrahydrofuran (10mL). To this was added a solution of dimethyl5-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethoxy]isophthalate(synthesized in Example 24) (1.30 g) in tetrahydrofuran (15 mL) dropwiseat room temperature. The suspension was stirred for 3 hours. Water (0.16mL) was added to the suspension and it was stirred for 10 minutes. A 15%aqueous sodium hydroxide solution (0.16 mL) was added to the suspensionand it was stirred for 15 minutes. Diethyl ether was added to themixture, followed by addition of water (0.48 mL). The solution wasstirred for 30 minutes. The solution was dried over anhydrous magnesiumsulfate, filtered and the filtrate was then concentrated under reducedpressure. The resulting residue was purified by chromatography [silicagel, ethyl acetate] to give the title compound (1.04 g).

¹H-NMR (CDCl₃) δ: 1.03 (s, 9H), 1.26-1.30 (m, 2H), 1.35-1.45 (m, 8H),1.66 (t, 2H, J=7.3 Hz), 1.73-1.77 (t like, 2H), 3.74 (t, 2H, J=7.4 Hz),3.93 (t, 2H, J=7.3 Hz), 4.12 (q, 2H, J=7.3 Hz), 4.65 (s, 4H), 6.78 (s,2H), 6.92 (s, 1H), 7.34-7.40 (m, 6H), 7.66-7.71 (m, 4H).

EXAMPLE 31 2-[1-[2-(3,5-Diacetoxymethylphenyoxy)ethyl]cyclohexyl]ethanol

To a solution of1-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethoxy]-3,5-dihydroxymethylbenzene(synthesized in Example 30) (1.04 g) dissolved in pyridine (5.0 mL) wasadded acetic anhydride (5 mL) under ice cooling. The solution wasstirred for 1 hour. After allowing the temperature to rise to roomtemperature, the solution was stirred for additional 1 hour. Thereaction solution was concentrated under reduced pressure (by azeotropicdistillation with toluene) to give1-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethoxy]-3,5-diacetoxymethylbenzene(1.13 g). This product was subjected to the subsequent step withoutfurther purification.

To a solution of1-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethoxy]-3,5-diacetoxymethylbenzene(1.13 g) dissolved in tetrahydrofuran (7 mL) was added a 1Mtetrabutylammonium fluoride/tetrahydrofuran solution (2.8 mL) dropwiseat room temperature. The solution was stirred for 15 hours. A 10%aqueous citric acid solution was added to the solution, and it wasextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution. The organic layer was dried over anhydrousmagnesium sulfate and filtered. The filtrate was then concentrated underreduced pressure. The resulting residue was purified by chromatography[silica gel, hexane:ethyl acetate (1:1)] to give the title compound (439mg).

¹H-NMR (CDCl₃) δ: 1.35-1.54 (m, 11H), 1.68 (t, 2H, J=7.3 Hz), 1.83 (t,2H, J=7.3 Hz), 2.12 (s, 6H), 3.75 (t, 2H, J=7.3 Hz), 4.04 (t, 2H, J=7.3Hz), 5.07 (s, 4H), 6.85 (s, 2H), 6.92 (s, 1H).

EXAMPLE 321,3-Diacetoxymethyl-5-[2-[1-(formylmethyl)cyclohexyl]ethoxy]benzene

To a solution of2-[1-[2-(3,5-diacetoxymethylphenyoxy)ethyl]cyclohexyl]ethanol(synthesized in Example 31) (430 mg) dissolved in dichloromethane (5 mL)were added diacetic acid iodobenzene (388 mg) and2,2,6,6-tetramethyl-1-piperidinyloxy free radical (18.5 mg) successivelyat room temperature. The solution was stirred for 15 hours. Diethylether was added to the solution and it was washed in turn with a 10%aqueous sodium thiosulfate solution, 1N hydrochloric acid, saturatedaqueous sodium bicarbonate solution and saturated aqueous sodiumchloride solution. The organic layer was dried over anhydrous magnesiumsulfate, and filtered. The filtrate was then concentrated under reducedpressure to give the title compound (479 mg). This product was subjectedto the subsequent step without further purification.

EXAMPLE 331,3-Diacetoxymethyl-5-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzene

1,3-Diacetoxymethyl-5-[2-[1-(formylmethyl)cyclohexyl]ethoxy]benzene(synthesized in Example 32) (215 mg) and 4-(p-toluidino)piperidine(synthesized in Preparation Example 4-5) (127 mg) were dissolved in1,2-dichloroethane (5 mL). To this was added acetic acid (0.04 mL) atroom temperature. The solution was stirred for 45 minutes. Sodiumtriacetoxyborohydride (294 mg) was added to the solution at roomtemperature. The solution was stirred for 3 hours. saturated aqueoussodium bicarbonate solution was added to the solution and it wasextracted with chloroform. The organic layer was dried over anhydrousmagnesium sulfate, and filtered. The filtrate was then concentratedunder reduced pressure. The resulting residue was purified bychromatography [silica gel, chloroform-methanol (10:1)] to give thetitle compound (334 mg). This product was subjected to the subsequentstep without further purification.

¹H-NMR (CDCl₃) δ: 1.27-1.48 (m, 14H), 1.49-1.82 (m, 7H), 2.11 (s, 6H),2.22 (s, 3H), 2.31-2.43 (m, 2H), 2.83-2.98 (m, 2H), 3.21-3.33 (m, 1H),3.98-4.02 (m, 2H), 5.07 (s, 4H), 6.52 (d, 2H, J=8.3 Hz), 6.84 (s, 2H),6.91 (s, 1H), 6.96 (d, 2H, J=7.8 Hz).

EXAMPLE 34N-[1-[2-[1-[2-[3,5-Bis(hydroxymethyl)phenoxy]ethyl]cyclohex-yl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution of1,3-diacetoxymethyl-5-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzene(synthesized in Example 33) (222 mg) dissolved in dichloromethane (4 mL)was added triethylamine (0.11 mL). 2-Furoyl chloride (0.06 mL) was addedto the solution under ice cooling. The temperature was allowed to riseto room temperature, and the solution was stirred for 1 hour. Thereaction solution was concentrated under reduced pressure. The resultingresidue was purified by chromatography [silica gel, chloroform-methanol(10:1)] to giveN-[1-[2-[1-[2-[3,5-bis(acetoxymethyl)phenoxy]ethyl]cyclohex-yl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(276 mg). This product was subjected to the subsequent step withoutfurther purification.

To a solution ofN-[1-[2-[1-[2-[3,5-bis(acetoxymethyl)phenoxy]ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(276 mg) dissolved in methanol (4 mL) was added potassium carbonate (11mg). The solution was stirred at room temperature for 2 hours. Thereaction solution was concentrated under reduced pressure. Saturatedaqueous sodium bicarbonate solution was added to the solution, and itwas extracted with chloroform-ethanol (80:20). The organic layer wasdried over anhydrous magnesium sulfate, and filtered. The filtrate wasthen concentrated under reduced pressure to give the title compound (228mg).

Free Form

¹H-NMR (CDCl₃): 1.26-1.32 (m, 4H), 1.32-1.58 (m, 10H), 1.73-1.77 (m,4H), 1.85 (brd, 2H, J=11.2 Hz), 2.12 (t, 2H, J=11.7 Hz), 2.28-2.41 (m,2H), 2.39 (s, 3H), 2.97 (d, 2H, J=11.2 Hz), 3.99 (t, 2H, J=7.3 Hz), 4.63(s, 4H), 4.71-4.77 (m, 1H), 5.38 (s, 1H), 6.13 (dd, 1H, J=1.9 Hz, 3.4Hz), 6.82 (s, 2H), 6.89 (s, 1H), 7.01 (d, 2H, J=8.3 Hz), 7.18 (d, 1H,J=7.8 Hz), 7.34 (s, 1H).

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.26-1.50 (m, 10H), 1.55-1.72 (m, 6H), 2.01-2.04 (m,2H), 2.39 (s, 3H), 2.95-3.03 (m, 2H), 3.10-3.18 (m, 2H), 3.54 (d, 2H,J=10.8 Hz), 3.97-4.01 (m, 2H), 4.45 (s, 4H), 4.77-4.83 (t like, 1H),5.07-5.20 (m, 2H), 5.43 (s, 1H), 6.31 (d, 1H, J=1.4 Hz), 6.75 (s, 2H),6.87 (s, 1H), 7.16 (d, 2H, J=7.8 Hz), 7.30 (d, 2H, J=8.3 Hz), 7.64 (s,1H); IR (KBr) cm⁻¹ 3388, 2926, 1731, 1616, 1511, 1467, 1404, 1340, 1294,1245, 1165, 1031, 954, 842, 766; MS (ESI) m/z 575 (MH⁺).

EXAMPLE 35 Methyl2-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethoxy]benzoate

To a solution of methyl salicylate (456 mg) and potassium carbonate (498mg) in N,N-dimethylformamide (10 mL) was addedtert-butyl[2-[1-(2-iodoethyl)cyclohexyl]ethoxy]diphenylsilane(synthesized in Preparation Example 3A-3) (1.7 g). The solution washeated at 80° C. with stirring for 24 hours. Water was added to thereaction solution and it was extracted with ether. The ether layer waswashed with water and saturated aqueous sodium chloride solution. Theether layer was dried over anhydrous magnesium sulfate, and filtered.The filtrate was the concentrated under reduced pressure. The resultingresidue was purified by chromatography [silica gel, hexane-ethyl acetate(10:1)] to give the title compound (547 mg).

¹H-NMR (CDCl₃) δ: 1.02 (s, 9H), 1.27-1.48 (m, 10H), 1.65 (t, 2H, J=7.3Hz), 1.80 (t, 2H, J=7.6 Hz), 3.73 (t, 2H, J=7.3 Hz), 3.84 (s, 3H), 3.96(t, 2H, J=7.6 Hz), 6.85-7.00 (m, 2H), 7.32-7.45 (m, 7H), 7.63-7.69 (m,4H), 7.75 (dd, 1H, J=2.0 Hz, 7.8 Hz).

EXAMPLE 36 Methyl 2-[2-[1-(2-hydroxyethyl)cyclohexyl]ethoxy]benzoate

To a solution of methyl2-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethoxy]benzoate(synthesized in Example 35) (547 mg) in tetrahydrofuran (4 mL) was addeda 1M tetrabutyl ammonium fluoride/tetrahydrofuran solution (1 mL) atroom temperature. The solution was then stirred for 2 hours. Thereaction solution was concentrated under reduced pressure. The resultingresidue was purified by chromatography [silica gel, hexane-ethyl acetate(2:1)] to give the title compound (226 mg).

¹H-NMR (CDCl₃) δ: 1.28-1.52 (m, 10H), 1.75 (t, 2H, J=7.6 Hz), 1.90 (t,2H, J=6.1 Hz), 2.30 (brs, 1H), 3.74 (t, 2H, J=7.6 Hz), 3.88 (s, 3H),4.12 (t, 2H, J=6.1 Hz), 6.94-7.00 (m, 2H), 7.42-7.48 (m, 1H), 7.77 (dd,1H, J=2.0 Hz, 7.8 Hz).

EXAMPLE 37 Methyl 2-[2-[1-(formylmethyl)cyclohexyl]ethoxy]benzoate

To a solution of methyl2-[2-[1-(2-hydroxyethyl)cyclohexyl]ethoxy]benzoate (synthesized inExample 36) (226 mg) and 2,2,6,6-tetramethyl-1-piperidinyloxy freeradical (23 mg) in dichloromethane (4 mL) was added diacetic acidiodobenzene (261 mg) at room temperature. The solution was stirred atroom temperature for 48 hours. Silica gel was added to the reactionsolution and it was concentrated under reduced pressure. The resultingresidue was purified by chromatography [silica gel, hexane-ethyl acetate(5:1)] to give the title compound (118 mg).

¹H-NMR (CDCl₃) δ: 1.40-1.60 (m, 10H), 2.05 (t, 2H, J=6.6 Hz), 2.51 (d,2H, J=2.9 Hz), 3.86 (s, 3H), 4.15 (t, 2H, J=6.6 Hz), 6.95-7.00 (m, 2H),7.42-7.48 (m, 1H), 7.75 (dd, 1H, J=1.4 Hz, 7.8 Hz), 9.90 (t, 1H, J=2.9Hz).

EXAMPLE 38 Methyl2-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]-ethoxy]benzoate

To a solution of methyl 2-[2-[1-(formylmethyl)cyclohexyl]ethoxy]benzoate(synthesized in Example 37) (118 mg), 4-(p-toluidino)piperidineditrifluoroacetate (synthesized in Preparation example 4-5) (194 mg),1,2-dichloroethane (2 mL) and triethylamine (94 mg) were added aceticacid (28 mg) and sodium triacetoxyborohydride (115 mg) at roomtemperature. After completion of addition, the solution was stirred atroom temperature for 2 hours. The reaction solution was purified bychromatography [the upper layer: NH silica gel, and the lower layer:silica gel, chloroform-ethanol (20:1)] to give the title compound (205mg).

EXAMPLE 39 Methyl2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamidopiperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzoate

To a solution of methyl2-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]-ethoxy]benzoate(synthesized in Example 38) (186 mg) and triethylamine (0.081 mL) indichloromethane (2 mL) was added 2-furoyl chloride (0.046 mL) dropwiseunder ice cooling. After completion of the dropwise addition, thesolution was stirred for 18 hours while the temperature was allowed torise to room temperature. NH silica gel was added to the reactionsolution and it was concentrated under reduced pressure. The resultingresidue was purified by chromatography [NH silica gel, hexane-ethylacetate (3:1)] to give the title compound (223 mg).

¹H-NMR (CDCl₃) δ: 1.30-1.58 (m, 14H), 1.80-1.90 (m, 4H), 2.05-2.14 (m,2H), 2.25-2.32 (m, 2H), 2.39 (s, 3H), 2.94-3.00 (m, 2H), 3.87 (s, 3H),4.00-4.06 (m, 2H), 4.72-4.82 (m, 1H), 5.33-5.37 (m, 1H), 6.13 (dd, 1H,J=1.5 Hz, 3.9 Hz), 6.91-7.05 (m, 4H), 7.15-7.20 (m, 2H), 7.33-7.35 (m,1H), 7.39-7.45 (m, 1H), 7.76 (dd, 1H, J=2.0 Hz, 7.8 Hz)

EXAMPLE 402-[2-[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzoicacid

To a solution of methyl2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzoate(synthesized in Example 39) (221 mg) in methanol (5 mL) was added asodium hydroxide (77 mg) solution in water (3 mL) dropwise at roomtemperature. The solution was stirred for 18 hours. After neutralizingthe reaction solution with 2N hydrochloric acid, silica gel was added tothe solution. The solution was concentrated under reduced pressure. Theresulting residue was purified by chromatography [silica gel,chloroform-methanol (10:1)] to give the title compound (172 mg).

Hydrochloride

¹H-NMR (CDCl₃) δ: 1.30-1.52 (m, 10H), 1.83-1.90 (m, 2H), 1.93-2.10 (m,6H), 2.17-2.30 (m, 2H), 2.42 (s, 3H), 3.00-3.12 (m, 2H), 3.53-3.62 (m,2H), 4.25-4.32 (m, 2H), 4.98-5.08 (m, 1H), 5.32-5.36 (m, 1H), 6.16-6.18(m, 1H), 7.01-7.08 (m, 3H), 7.14-7.19 (m, 1H), 7.23-7.29 (m, 4H),7.39-7.41 (m, 1H), 7.42-7.54 (m, 1H), 7.95-8.00 (m, 1H), 11.81 (brs,1H).

EXAMPLE 41N-[1-[2-[1-[2-(2-Methyl-2H-tetrazol-5-yl)ethyl]cyclohexyl]-ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

N-[1-[2-[1-[2-(1-Methyl-1H-tetrazol-5-yl)]ethyl]cyclohexyl]-ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

N-[1-[2-[1-(2-Tetrazolyethyl)cyclohexyl]ethyl]piperi-din-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide(synthesized in Example 4D-7) (228 mg) was dissolved in methanol (0.065mL) and benzene (3.25 mL). To this was added trimethylsilyldiazomethane(0.30 mL) under ice cooling. After allowing the temperature to rise toroom temperature, the solution was stirred for 19 hours.Trimethylsilyldiazomethane (0.60 mL) was further added to the solutionat room temperature and it was stirred for 75 hours.Trimethylsilyldiazomethane (1.12 mL) was further added and the solutionwas stirred for 24 hours. The reaction solution was concentrated underreduced pressure. The resulting residue was purified by chromatography[NH silica gel, hexane-ethyl acetate (1:1) to ethyl acetate] to give thetitle compound,N-[1-[2-[1-[2-(2-methyl-2H-tetrazol-5-yl)ethyl]cyclohexyl]-ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,as a low polarity fraction (151 mg) and also to give the title compound,N-[1-[2-[1-[2-(1-methyl-1H-tetrazol-5-yl)ethyl]cyclohexyl]-ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide,as a high polarity fraction (55 mg).

N-[1-[2-[1-[2-(2-Methyl-2H-tetrazol-5-yl)ethyl]cyclohexyl]-ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

¹H-NMR (CDCl₃): 1.26-1.51 (m, 14H), 1.70-1.73 (m, 2H), 1.95 (d, 2H,J=11.7 Hz), 2.10 (t, 2H, J=11.2 Hz), 2.29 (m, 2H), 2.38 (s, 3H),2.74-2.79 (m, 2H), 2.99 (d, 2H, J=11.7 Hz), 4.29 (s, 3H), 4.74 (t like,1H), 5.93 (d, 1H, J=3.4 Hz), 6.19 (dd, 1H, J=2.0 Hz, 3.4 Hz), 6.99 (d,1H, J=8.3 Hz), 7.22 (d, 1H, J=1.0 Hz) 7.50 (dd, 1H, J=1.9 Hz, 8.8 Hz),8.37 (d, 1H, J=1.9 Hz).

N-[1-[2-[1-[2-(1-Methyl-1H-tetrazol-5-yl)ethyl]cyclohexyl]-ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

¹H-NMR (CDCl₃) δ: 1.26-1.52 (m, 14H), 1.75-1.78 (m, 2H), 1.95 (d, 2H,J=12.2 Hz), 2.10 (t, 2H, J=11.2 Hz), 2.29 (m, 2H), 2.39 (s, 3H),2.70-2.74 (m, 2H), 2.99 (d, 2H, J=11.2 Hz), 3.98 (s, 3H), 4.72 (t like,1H), 5.94 (d, 1H, J=3.4 Hz), 6.19 (dd, 1H, J=2.0 Hz, 3.4 Hz), 6.98 (d,1H, J=8.3 Hz), 7.22 (d, 1H, J=1.0 Hz) 7.51 (dd, 1H, J=2.0 Hz, 8.3 Hz),8.37 (d, 1H, J=2.4 Hz).

EXAMPLE 42N-[1-[2-[1-(1,1-Dimethylcarbamoylmethyl)cyclohexyl]ethyl]-piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

To a solution of[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]aceticacid (synthesized in Example 3A-3) (300 mg) in dichloromethane (4 mL)was added N,N-dimethylformamide (1 drop) dropwise and then oxalylchloride (0.087 mL) under ice cooling. The solution was stirred underice cooling for 2 hours. A 2 mL aliquot of the reaction solution wastaken and it was added to a 50% aqueous dimethylamine solution (2 mL)dropwise. The solution was stirred for 18 hours while the temperaturewas allowed to rise to room temperature. NH Silica gel was then added tothe reaction solution and it was concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography[NH silica gel, hexane-ethyl acetate (1:1)] to give the title compound(90 mg).

Hydrochloride

¹H-NMR (CDCl₃) δ: 1.25-1.56 (m, 10H), 2.03-2.12 (m, 2H), 2.23 (s, 2H),2.25-2.46 (m, 4H), 2.57 (s, 3H), 2.85-3.15 (m, 10H), 3.52-3.60 (m, 2H),4.95-5.05 (m, 1H), 6.34 (dd, 1H, J=1.9 Hz, 3.4 Hz), 6.85 (d, 1H, J=3.4Hz), 7.12-7.15 (m, 1H), 7.52-7.58 (m, 1H), 8.12-8.18 (m, 1H), 8.51-8.54(m, 1H), 11.81 (brs, 1H).

EXAMPLE 43N-[1-[2-[1-(2-Morpholin-4-yl-2-oxoethyl)cyclohexyl]ethyl]-piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

To a solution of[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]aceticacid (synthesized in Example 3A-3) (300 mg) in dichloromethane (4 mL)was added N,N-dimethylfommamide (1 drop) dropwise and then oxalylchloride (0.087 mL) under ice cooling. The solution was stirred underice cooling for 2 hours. A 2 mL aliquot of the reaction solution wastaken and it was added to a solution of morpholine (288 mg) indichloromethane (4 mL) dropwise under ice cooling. The solution wasstirred under ice cooling for 1.5 hours. NH silica gel was then added tothe reaction solution and it was concentrated under reduced pressure.The residue was purified by chromatography [NH silica gel, hexane-ethylacetate (1:1)] to give the title compound (60 mg).

Hydrochloride

¹H-NMR (CDCl₃) δ: 1.20-1.60 (m, 10H), 2.03-2.11 (m, 2H), 2.23 (s, 2H),2.25-2.42 (m, 4H), 2.53 (s, 3H), 3.05-3.20 (m, 4H), 3.21-3.30 (m, 4H),3.50-3.75 (m, 4H), 4.00-4.05 (m, 2H), 4.92-5.08 (m, 1H), 6.30-6.34 (m,1H), 6.52-6.56 (m, 1H), 7.20 (s, 1H), 7.45-7.55 (m, 1H), 7.98-8.05 (m,1H), 8.51 (s, 1H), 11.59 (brs, 1H).

EXAMPLE 44N-[1-[2-[1-[2-(1,2-Di-tert-butoxycarbonylguanidino)ethyl]-cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

To a solution ofN-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide(synthesized in Example 3F-5) (104 mg) and1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (85 mg) inN,N-dimethylformamide (5 mL) were added N,N-diisopropylethylamine (0.12g) and then mercury (II) chloride (113 mg) at room temperature. Thesolution was stirred at room temperature for 3 days. Dichloromethane wasadded to the solution and insolubles were filtered off with Celite. Thesolvent was distilled off under reduced pressure. The resulting residuewas purified by chromatography [silica gel,dichloromethane-methanol-aqueous ammonia (97:3:0.2)] to give the titlecompound (0.1049 g).

¹H-NMR (DMSO-d₆) δ: 1.14-1.54 (m, 18H), 1.39 (s, 9H), 1.47 (s, 9H),1.70-1.79 (m, 2H), 1.90-2.01 (m, 2H), 2.21-2.28 (m, 2H), 2.34 (s, 3H),2.88-2.94 (m, 2H), 4.39-4.48 (m, 1H), 5.84 (d, 1H, J=3.4 Hz), 6.32 (dd,1H, J=2.0 Hz, 3.4 Hz), 7.15 (d, 1H, J=7.9 Hz), 7.52 (d, 1H, J=2.0 Hz),7.66 (dd, 1H, J=2.4 Hz, 7.9 Hz), 8.08-8.11 (m, 1H), 8.34 (d, 1H, J=2.4Hz), 11.20-11.22 (m, 1H).

EXAMPLE 45N-[1-[2-[1-(2-Guanidinoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

N-[1-[2-[1-[2-(1,2-Di-tert-butoxycarbonylguanidino)ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide(synthesized in Example 44) (105 mg) was dissolved in a 4N hydrochloricacid/1,4-dioxane solution (12 mL) and methanol (5 mL). The solution wasstirred at room temperature for 2 days. The solvent was distilled offunder reduced pressure and the resulting residue was crystallized (frommethanol-ethyl acetate) to give the title compound (69 mg).

Hydrochloride

mp 156-160° C.; ¹H-NMR (DMSO-d₆) δ: 1.18-1.51 (m, 12H), 1.58-1.69 (m,2H), 1.83-1.96 (m, 2H), 1.97-2.08 (m, 2H), 2.37 (s, 3H), 2.90-3.03 (m,2H), 3.04-3.20 (m, 4H), 3.49-3.59 (m, 2H), 4.70-4.80 (m, 1H), 5.89 (d,1H, J=3.4 Hz), 6.35 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.24 (d, 1H, J=7.8 Hz),7.56 (d, 1H, J=1.5 Hz), 7.57-7.65 (m, 1H), 7.73 (dd, 1H, J=2.0 Hz, 7.8Hz), 8.39 (d, 1H, J=2.0 Hz); IR (KBr) cm⁻¹: 3365, 3178, 2927, 2855,2714, 1651, 1469, 1403, 1386, 1340, 1321, 1191, 1032, 768, 754; MS (ESI)m/z: 481 (MH⁺).

EXAMPLE 462-[2-[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetylamino]benzoicacid

To a solution of[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]aceticacid (synthesized in Example 3A-3) (210 mg) in dichloromethane (2 mL)was added N,N-dimethylformamide (1 drop) dropwise and then oxalylchloride (0.038 mL) under ice cooling. The solution was stirred underice cooling for 2 hours. Methyl anthranylate (242 mg) was then addeddropwise to the solution, and it was stirred for 18 hours while thetemperature was allowed to rise to room temperature. NH Silica gel wasadded to the reaction solution and it was concentrated under reducedpressure. The resulting residue was purified by chromatography [silicagel, chloroform-ethanol (20:1)] to give methyl2-[2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetylamino]benzoate(150 mg).

To a solution of this product in methanol (5 mL) was added a solution ofsodium hydroxide (77 mg) in water (3 mL) dropwise at room temperature.The solution was stirred at room temperature for 18 hours. Afterneutralizing the solution with 2N hydrochloric acid, silica gel wasadded to the solution and it was concentrated under reduced pressure.The resulting residue was purified by chromatography [silica gel,chloroform-methanol (8:1)] to give the title compound (60 mg).

¹H-NMR (CDCl₃) δ: 1.30-1.60 (m, 10H), 1.80-1.90 (m, 2H), 2.00-2.20 (m,4H), 2.23 (s, 3H), 2.30 (s, 2H), 2.74-2.86 (m, 2H), 3.08-3.18 (m, 2H),3.50-3.60 (m, 2H), 4.82-4.92 (m, 1H), 5.87-5.90 (m, 1H), 6.18 (dd, 1H,J=1.5 Hz, 3.5 Hz), 6.91 (d, 1H, J=7.8 Hz), 6.98-7.04 (m, 1H), 7.21-7.23(m, 1H), 7.34-7.41 (m, 2H), 7.88 (dd, 1H, J=1.5 Hz, 7.8 Hz), 8.16-8.19(m, 1H), 8.57 (d, 1H, J=8.3 Hz), 12.71 (brs, 1H).

EXAMPLE 471,3-Diacetoxymethyl-5-[2-[1-[2-[4-(5-methylpyridin-2-yl-amino)piperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzene

1,3-Diacetoxymethyl-5-[2-[1-(formylmethyl)cyclohexyl]ethoxy]benzene(synthesized in Example 32) (215 mg) and2-(piperidin-4-ylamino)-5-methylpyridine (synthesized in PreparationExample 4-3) (126 mg) were dissolved in 1,2-dichloroethane (5 mL). Tothis was added acetic acid (0.04 mL) at room temperature. The solutionwas stirred for 45 minutes. Sodium triacetoxyborohydride (295 mg) wasadded to the solution at room temperature and it was stirred for 3hours. Saturated aqueous sodium bicarbonate solution was added to thesolution and it was extracted with chloroform. The organic layer wasdried over anhydrous magnesium sulfate, and filtered. The filtrate wasthen concentrated under reduced pressure. The resulting residue waspurified by chromatography [silica gel, chloroform-methanol (10:1)] togive the title compound (258 mg).

¹H-NMR (CDCl₃): 1.26-1.54 (m, 10H), 1.57-1.61 (m, 4H), 1.80 (t, 2H,J=7.3 Hz), 2.05-2.10 (brd, 2H, J=7.3 Hz), 2.11 (s, 6H), 2.16 (s, 3H),2.21-2.27 (m, 2H), 2.40 (t, 2H, J=7.8 Hz), 2.92-3.00 (m, 2H), 3.56-3.68(m, 1H), 4.01 (t, 2H, J=7.3 Hz), 4.27 (brd, 1H, J=7.8 Hz), 5.07 (s, 4H),6.30 (d, 1H, J=8.3 Hz), 6.84 (s, 2H), 6.91 (s, 1H), 7.23 (dd, 1H, J=2.5Hz, 8.3 Hz), 7.88 (s, 1H).

EXAMPLE 48N-[1-[2-[1-[2-[3,5-Bis(hydroxymethyl)phenoxy]ethyl]cyclohex-yl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

To a solution of1,3-diacetoxymethyl-5-[2-[1-[2-[4-(5-methylpyridin-2-yl-amino)piperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzene(synthesized in Example 47) (249 mg) dissolved in 1,2-dichloroethane (4mL) was added triethylamine (0.13 mL). 2-Furolyl chloride (0.065 mL) wasadded to the solution under ice cooling. The temperature was thenallowed to rise to room temperature and the solution was stirred for 1hour. The reaction solution was concentrated under reduced pressure. Theresulting residue was purified by chromatography [silica gel,chloroform-methanol (10:1)] to giveN-[1-[2-[1-[2-[3,5-bis(acetoxymethyl)phenoxy]ethyl]cyclohex-yl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide(303 mg).

To a solution of this product in methanol (4 mL) was added potassiumcarbonate (12 mg). The solution was stirred at room temperature for 2hours. The reaction solution was concentrated under reduced pressure.Saturated aqueous sodium bicarbonate solution was then added to theresidue and it was extracted with chloroform-ethanol (80:20). Theorganic layer was dried over anhydrous magnesium sulfate, and filtered.The filtrate was then concentrated under reduced pressure to give thetitle compound (248 mg).

Free Form

¹H-NMR (CDCl₃) δ: 1.25-1.51 (m, 14H), 1.56-1.64 (m, 2H), 1.73-1.77 (m,2H), 1.92 (d, 2H, J=11.2 Hz), 2.07-2.12 (t like, 2H), 2.28-2.32 (m, 2H),2.37 (s, 3H), 2.97 (d, 2H, J=11.2 Hz), 3.97-4.00 (t like, 2 Hz), 4.60(s, 4H), 4.65-4.73 (m, 1H), 5.94 (d, 1H, J=3.4 Hz), 6.19 (dd, 1H, J=2.0Hz, 3.4 Hz), 6.80 (s, 2H), 6.86 (s, 1H), 6.98 (d, 1H, J=7.8 Hz), 7.22(s, 1H), 7.50 (dd, 1H, J=2.4 Hz, 7.8 Hz), 8.36 (s, 1H).

Hydrochloride

¹H-NMR (DMSO-d₆): 1.32-1.44 (m, 10H), 1.63-1.71 (m, 4H), 1.82-1.91 (m,2H), 1.99-2.06 (m, 2H), 2.37 (s, 3H), 3.01-3.06 (m, 2H), 3.08-3.22 (m,2H), 3.46-3.70 (m, 4H), 3.97-4.03 (m, 2H), 4.45 (s, 4H), 4.76 (t like,1H), 5.87 (d, 1H, J=3.4 Hz), 6.35 (dd, 1H, J=2.0 Hz, 3.4 Hz), 6.75 (s,2H), 6.83 (s, 1H), 7.24 (d, 1H, J=8.3 Hz), 7.56 (s, 1H), 7.73 (dd, 1H,J=2.4 Hz, 7.8 Hz), 8.40 (s, 1H), 9.50-9.60 (brm, 1H); IR (KBr) cm⁻¹3388, 2927, 1731, 1633, 1595, 1469, 1401, 1324, 1294, 1161, 1031, 754;MS (ESI) m/z 576 (MH⁺).

EXAMPLE 49N-[1-[2-[1-[5-Hydroxy-3,3-bis(hydroxymethyl)pentyl]cyclohex-yl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

mp 122-125° C.; ¹H-NMR (DMSO-d₆) δ: 1.04-1.15 (m, 4H), 1.15-1.23 (m,4H), 1.34-1.39 (m, 8H), 1.55-1.59 (m, 2H), 1.83-1.92 (m, 2H), 2.02 (d,2H, J=12.7 Hz), 2.37 (s, 3H), 2.92-3.02 (m, 2H), 3.01-3.11 (m, 2H),3.19-3.25 (m, 4H), 3.44-3.49 (m, 4H), 4.75 (m, 1H), 5.90 (d, 1H, J=3.4Hz), 6.35 (dd, 1H, J=1.9 Hz, 3.4 Hz), 7.24 (d, 1H, J=7.8 Hz), 7.56 (d,1H, J=1.0 Hz), 7.74 (dd, 1H, J=1.5 Hz, 7.8 Hz), 8.39 (d, 1H, J=1.9 Hz),9.54-9.71 (brs, 1H); IR (KBr) cm⁻¹: 3417, 2926, 1633, 1557, 1469, 1385,1319, 1190, 1017; Anal. Calcd for C₃₁H₄₉Cl₂N₃O₅ 1/2H₂O: C, 59.70; H,8.08; N, 6.74 Found: C, 59.50; H, 8.33; N, 6.95.

EXAMPLE 50N-[1-[2-[1-(4-Hydroxy-3-hydroxymethylbutyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide

mp 115-117° C.; ¹H-NMR (DMSO-d₆) δ: 1.15-1.24 (m, 8H), 1.24-1.39 (m,8H), 1.51-1.66 (m, 2H), 1.85-1.94 (m, 2H), 2.00-2.03 (m, 2H), 2.37 (s,3H), 2.84-2.95 (m, 2H), 3.05-3.13 (m, 2H), 3.34-3.42 (m, 4H), 3.49 (d,2H, J=11.7 Hz), 4.75 (t-like, 1H), 5.89 (d, 1H, J=3.4 Hz), 6.36 (dd, 1H,J=1.5 Hz, 3.4 Hz), 7.24 (d, 1H, J=8.3 Hz), 7.56 (d, 1H, J=1.0 Hz), 7.74(dd, 1H, J=1.4 Hz, 8.3 Hz), 8.40 (s, 1H), 9.83-9.94 (m, 1H); IR (KBr)cm⁻¹: 3417, 2927, 2645, 1651, 1633, 1557, 1470, 1385, 1320, 1190, 1032,768; Anal. Calcd for C₂₉H₄₅Cl₂N₃O₄: C, 60.95; H, 7.95; N, 7.35 Found: C,61.75; H, 8.56; N, 7.43.

EXAMPLE 512-[1-[2-[4-(p-Toluidino)piperidin-1-yl]ethyl]cyclohexyl]eth-anol

The title compound was synthesized from the compound obtained inPreparation Example 1F-1 and the compound obtained in PreparationExample 4-5 in the same manner as in Example 1F-1.

¹H-NMR (CDCl₃) δ: 1.26-1.32 (m, 4H), 1.32-1.52 (m, 10H), 1.53 (t, 2H,J=6.4 Hz), 1.58 (t, 2H, J=6.3 Hz), 2.03 (d, 2H, J=7.3 Hz), 2.13 (t, 2H,J=10.7 Hz), 2.23 (s, 3H), 2.32 (t, 2H, J=6.3 Hz), 2.91 (d, 2H, J=10.3Hz), 3.28 (t, 1H, J=10.3 Hz), 3.68 (t, 2H, J=6.3 Hz), 6.51 (d, 2H, J=8.3Hz), 6.96 (d, 2H, J=8.3 Hz); MS (ESI) m/z: 346 (MH⁺).

EXAMPLE 522-[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]ethyl2-furancarboxylate

The title compound was synthesized from2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]eth-anol(synthesized in Example 51) in the same manner as in Example 2-31.

Hydrochloride

¹H-NMR (DMSO-d₆) δ: 1.23-1.42 (m, 11H), 1.60-1.66 (m, 6H), 2.02 (d, 2H,J=13.2 Hz), 2.37 (s, 3H), 2.96-2.99 (m, 2H), 3.08-3.16 (m, 2H),3.50-3.53 (m, 2H), 4.27 (t, 2H, J=7.3 Hz), 4.76 (t, 1H, J=12.2 Hz), 5.49(s, 1H), 6.32 (dd, 1H, J=1.4 Hz, 3.4 Hz), 6.67 (dd, 1H, J=2.0 Hz, 3.4Hz), 7.15 (d, 2H, J=7.8 Hz), 7.26 (d, 1H, J=3.4 Hz), 7.29 (d, 2H, J=7.8Hz), 7.63 (s, 1H), 7.94 (s, 1H), 9.40-9.60 (brs, 1H).

EXAMPLE 53N-[1-[2-[1-(2-Hydroxyethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

The title compound was synthesized from 2-furancarboxylic acid2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]ethylester (synthesized in Example 52) in the same manner as in Example 3C-4.

¹H-NMR (CDCl₃): 1.24-1.29 (m, 4H), 1.30-1.48 (m, 9H), 1.51-1.55 (m, 4H),1.85 (d, 2H, J=12.7 Hz), 2.11 (t, 2H, J=11.7 Hz), 2.26 (t, 2H, J=6.8Hz), 2.39 (s, 3H), 2.98 (d, 2H, J=11.7 Hz), 3.60 (t, 2H, J=6.8 Hz), 4.75(tt, 1H, J=3.9 Hz, 12.2 Hz), 5.35 (d, 1H, J=2.9 Hz), 6.13 (dd, 1H, J=2.0Hz, 3.4 Hz), 7.00 (d, 2H, J=8.3 Hz), 7.18 (d, 2H, J=7.8 Hz), 7.34 (d,1H, J=1.0 Hz); MS (ESI) m/z: 439 (MH⁺).

EXAMPLE 54N-[1-[2-[1-Carbamoylmethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

The title compound was synthesized from the compound synthesized inExample 3B-1 in the same manner as in Example 4D-1.

¹H-NMR (CDCl₃) δ: 1.23-1.28 (t-like, 2H), 1.31-1.53 (m, 10H), 1.56 (t,2H, J=5.9 Hz), 1.88 (d, 2H, J=13.1 Hz), 2.12 (s, 2H), 2.17 (t, 2H,J=11.2 Hz), 2.33 (t, 2H, J=5.8 Hz), 2.42 (s, 3H), 3.00 (d, 2H, J=11.7Hz), 4.77 (tt, 1H, J=3.9 Hz, 8.3 Hz), 5.01-5.07 (m, 1H), 5.35 (s, 3H),6.14 (dd, 1H, J=1.5 Hz, 3.5 Hz), 6.99 (d, 2H, J=7.8 Hz), 7.20 (d, 2H,J=7.9 Hz), 7.35 (d, 1H, J=1.5 Hz), 7.67-7.75 (m, 1H); MS (ESI) m/z: 452(MH⁺).

EXAMPLE 55N-[1-[2-[1-(Cyanomethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

The title compound was synthesized fromN-[1-[2-[1-(1-carbamoylmethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(synthesized in Example 54) in the same manner as in Example 4D-2.

¹H-NMR (CDCl₃): 1.26-1.57 (m, 14H), 1.87 (d, 2H, J=12.2 Hz), 2.12 (t,2H, J=10.7 Hz), 2.29 (t, 2H, J=7.8 Hz), 2.34 (s, 2H), 2.40 (s, 3H), 2.97(d, 2H, J=11.7 Hz), 4.77 (tt, 1H, J=3.9 Hz, 12.2 Hz), 5.35 (s, 1H), 6.13(dd, 1H, J=1.5 Hz, 3.5 Hz), 7.01 (d, 2H, J=8.3 Hz), 7.19 (d, 2H, J=7.8Hz), 7.35 (d, 1H, J=1.4 Hz); MS (ESI) m/z: 434 (MH⁺).

EXAMPLE 56 Methyl4-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]-butyrate

The title compound was synthesized from the compound obtained inPreparation Example 1F-3 and the compound obtained in PreparationExample 4-5 in the same manner as in Example 1F-1. This product wassubjected to the subsequent step without further purification.

EXAMPLE 57 MethylN-[1-[2-[4-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]butyrate

The title compound was synthesized from methyl4-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]-butyrate(synthesized in Example 56) in the same manner as in Example 2-16.

¹H-NMR (CDCl₃) δ: 1.18-1.28 (m, 6H), 1.30-1.48 (m, 10H), 1.50-1.56 (m,2H), 1.85 (d, 2H, J=12.7 Hz), 2.10 (t, 2H, J=11.7 Hz), 2.22-2.29 (m,4H), 2.39 (s, 3H), 2.97 (d, 2H, J=11.7 Hz), 3.67 (s, 3H), 4.77 (t, 1H,J=11.8 Hz), 5.35 (m, 1H), 6.13 (dd, 1H, J=1.4 Hz, 3.4 Hz), 7.01 (d, 2H,J=8.3 Hz), 7.18 (d, 2H, J=7.9 Hz), 7.35 (s, 1H).

EXAMPLE 584-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]butyricacid

The title compound was synthesized from methyl4-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]butyrate(synthesized in Example 57) in the same manner as in Example 3C-1.

¹H-NMR (CDCl₃) δ: 1.15-1.26 (m, 6H), 1.26-1.44 (m, 8H), 1.45-1.49 (m,2H), 1.66-1.75 (m, 2H), 1.88 (d, 2H, J=11.2 Hz), 1.98 (t, 2H, J=7.8 Hz),2.34-2.46 (m, 5H), 2.50-2.54 (m, 2H), 3.34 (d, 2H, J=111.7 Hz), 4.83 (t,1H, J=12.7 Hz), 5.36 (d, 1H, J=2.9 Hz), 6.14 (dd, 1H, J=1.5 Hz, 3.4 Hz),6.99 (d, 2H, J=8.3 Hz), 7.19 (d, 2H, J=7.8 Hz), 7.36 (d, 1H, J=1.4 Hz).

EXAMPLE 59 Triethyl3-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]-1,1,1-propanetricarboxylate

The title compound was synthesized from the compound obtained inPreparation Example 3A-6 and the compound obtained in PreparationExample 4-5 in the same manner as in Example 1D-5. This product wassubjected to the subsequent step without further purification.

EXAMPLE 60 Triethyl3-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]-ethyl]cyclohexyl]-1,1,1-propanetricarboxylate

The title compound was synthesized from triethyl3-[1-[2-[4-(p-tolyl)piperidin-1-yl]ethyl]cyclohexyl]-1,1,1-propanetricarboxylate(synthesized in Example 59) in the same manner as in Example 2-17.

¹H-NMR (CDCl₃) δ: 1.20-1.32 (m, 13H), 1.32-1.43 (m, 10H), 1.47-1.66 (m,2H), 1.85 (d, 2H, J=10.8 Hz), 1.99-2.02 (m, 2H), 2.10 (t, 2H, J=10.7Hz), 2.22-2.26 (m, 2H), 2.39 (s, 3H), 2.98 (d, 2H, J=11.8 Hz), 4.24 (q,6H, J=7.3 Hz), 4.77 (t, 1H, J=3.4 Hz), 5.36 (s, 1H), 6.13 (dd, 1H, J=1.4Hz, 3.4 Hz), 7.01 (d, 2H, J=8.3 Hz), 7.18 (d, 2H, J=7.9 Hz), 7.35 (s,1H).

EXAMPLE 61 Ethyl Cyclobutylideneacetate

To an ice-cooled suspension of 60% sodium hydride (0.68 g) inN,N-dimethylformamide (20 mL) was added triethyl phosphonoacetate (3.4mL) dropwise over 5 minutes. After stirring the suspension under icecooling for 30 minutes, cyclobutanone (1.1 mL) was added dropwise over 5minutes. The solution was stirred under ice cooling for additional 1hour. The reaction solution was poured into saturated aqueous ammoniumchloride solution, and it was extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium chloride solution, driedover anhydrous magnesium sulfate and filtered. The filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby chromatography [silica gel, hexane-ethyl:acetate (20:1)] to give thetitle compound (1.27 g).

¹H-NMR (CDCl₃) δ: 1.27 (t, 3H, J=6.8 Hz), 2.04-2.13 (m, 2H), 2.82-2.85(m, 2H), 3.10-3.15 (m, 2H), 4.14 (q, 2H, J=6.8 Hz), 5.56-5.59 (m, 1H).

EXAMPLE 62 2-Cyclobutylidene ethyl acetate

To an ice-cooled solution of ethyl cyclobytylideneacetate (1.27 g) intetrahydrofuran (10 mL) was added a 1M diisobutylaluminum hydride/hexanesolution (27 mL) dropwise over 10 minutes. After stirring the solutionunder ice cooling for 1 hour, 1N hydrochloric acid (30 mL) was added tothe reaction solution. The temperature was allowed to rise to roomtemperature and the solution was stirred for additional 30 minutes. Thereaction solution was extracted with dichloromethane. The organic layerwas dried over anhydrous sodium sulfate and dried under reducedpressure. To the resulting residue were added pyridine (2 mL), aceticanhydride (2 mL) and N,N-dimethylaminopyridine (110 mg) successively.The solution was stirred at room temperature for 14 hours. The reactionsolution was diluted with ethyl acetate and washed in turn with3N-hydrochloric acid, saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution. The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The resulting residue was purified by chromatography [silica gel,hexane-ethyl acetate (50:1)] to give the title compound (0.98 g).

¹H NMR (CDCl₃) δ: 1.94-2.02 (m, 2H), 2.05 (s, 3H), 2.68-2.76 (m, 4H),4.44 (d, 2H, J=7.3 Hz), 5.25-5.30 (m, 1H).

EXAMPLE 63 Methyl (1-vinylcyclobutyl)acetate

To an ice-cooled solution of diisopropylamine (1.07 mL) in THF (10 mL)was added 1.57 M n-butyllithium/hexane (4.47 mL) dropwise over 5minutes. After stirring under ice cooling for additional 30 minutes, thereaction solution was cooled to −78° C. and a solution of2-cyclobutyridene ethyl acetate (0.89 g) in tetrahydrofuran (0.8 mL) wasadded thereto dropwise over 5 minutes. After stirring the reactionsolution at that temperature for 1 hour, chlorotrimethylsilane (0.97 mL)was added dropwise over 5 minutes. The reaction solution was stirred atroom temperature for 1 hour, and then, heated under reflux for 4.5hours. The reaction solution was ice-cooled, to which methanol (2 mL)and a 3N aqueous sodium hydroxide solution (5 ml) were added. Thesolution was stirred for 30 minutes. Then, conc. hydrochloric acid (2mL) was added to the solution and it was stirred for additional 30minutes. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting residue (1.77 g) wasdissolved in N,N-dimethylformamide (10 mL), to which potassium carbonate(2.82 g) and methyl iodide (0.62 mL) were added. The solution wasstirred at room temperature for 1 hour. The reaction solution wasfiltered with Celite and insolubles on Celite were washed with ethylacetate. The filtrate was combined with the wash, and it washed in turnwith 1N hydrochloric acid and saturated aqueous sodium chloridesolution. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby chromatography [silica gel, hexane-ethyl acetate (20:1)] to give thetitle compound (0.67 g).

¹H-NMR (CDCl₃) δ: 2.01-2.13 (m, 6H), 2.55 (s, 2H), 3.63 (s, 3H), 5.03(d, 1H, J=11.2 Hz), 5.04 (d, 1H, J=17.1 Hz), 5.99 (dd, 1H, J=10.7 Hz,17.6 Hz).

EXAMPLE 64 3-Oxaspiro[5.3]nonan-2-one

To an ice-cooled solution of methyl (1-vinylcyclobutyl)acetate (0.67 g)in tetrahydrofuran (3 mL) was added 0.5M9-borabicyclo[3.3.1]nonane/tetrahydrofuran (17.5 mL) dropwise over 10minutes. The reaction solution was then allowed for its temperature torise to room temperature and it was stirred for additional 9 hours. Thereaction solution was again ice-cooled and ethanol (4 mL), a 6N aqueoussodium hydroxide solution (8 mL) and 30% hydrogen peroxide (8 mL) weresuccessively added thereto. The reaction solution was then allowed forits temperature to rise to room temperature and it was stirred foradditional 30 minutes. The reaction solution was again ice-cooled. Afterconc. hydrochloric acid (5 mL) was added to the solution, it was stirredfor additional 30 minutes. The reaction solution was extracted withtert-butyl methyl ether. The organic layer was washed with saturatedaqueous sodium chloride solution, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The resulting residue waspurified by chromatography [silica gel, hexane-ethyl acetate (9:1)] togive the title compound (0.31 g).

¹H-NMR (CDCl₃) δ: 1.88-1.98 (m, 8H), 2.61 (s, 2H), 4.33 (t, 2H, J=5.9Hz).

EXAMPLE 65 3-Oxaspiro[5.3]nonan-2-ol

To a solution of 3-oxaspiro[5.3]nonan-2-one (0.67 g) in tetrahedrofuran(3 mL) cooled at −78° C. was added 1M diisobutylaluminumhydride/tetrahydrofuran (1.0 mL) dropwise over 5 minutes. The reactionsolution was stirred at that temperature for 1.5 hours. Water (40 μL)was added to the reaction solution. After allowing the temperature torise to room temperature, a 15% aqueous sodium hydroxide solution (40μL) and water (120 μL) were successively added to the solution. Afterstirring the solution at room temperature for 10 minutes, diethyl ether(2 mL) and anhydrous magnesium sulfate (0.17 g) were added. The solutionwas stirred for additional 30 minutes. The reaction solution was thenfiltered with Celite. The filtrate was concentrated under reducedpressure to give the title compound (230 mg).

¹H-NMR (CDCl₃) δ: 1.32 (dd, 1H, J=7.8 Hz, 13.2 Hz), 1.42-1.46 (m, 2H),1.63-1.79 (m, 7H), 3.34-3.40 (m, 1H), 3.75-3.81 (m, 1H), 4.62 (dd, 1H,J=2.4 Hz, 7.8 Hz).

EXAMPLE 662-[1-[2-[4-(p-Toluidino)piperidin-1-yl]ethyl]cyclobutyl]eth-anol

To a suspension of 4-(p-toluidino)piperidine trifluoroacetate (418 mg)(synthesized in Preparation Example 4-5) in tetrahydrofuran (3 mL) wasadded triethylamine (0.28 mL). The solution was stirred at roomtemperature for 5 minutes. Then, 3-oxaspiro[5.3]nonan-2-ol (104 mg)(synthesized in Example 65) in tetrahydrofuran (3 mL) was added to thesolution and it was stirred at room temperature for additional 10minutes. The reaction solution was ice-cooled and sodiumtriacetoxyborohydride (424 mg) was added thereto. The solution was thenallowed for its temperature to rise to room temperature. The solutionwas stirred for additional 4.5 hours. A 3N aqueous sodium hydroxidesolution (5 mL) was added to the reaction solution and it was extractedwith tert-butyl methyl ether. The resulting residue was purified bychromatography [NH silica gel, hexane-ethyl acetate (7:3)] to give thetitle compound (175 mg).

¹H-NMR (CDCl₃) δ: 1.41-1.50 (m, 2H), 1.67-1.78 (m, 6H), 1.83-1.89 (m,2H), 2.02-2.17 (m, 4H), 2.22 (s, 3H), 2.29 (t, 2H, J=5.9 Hz), 2.87-2.94(m, 2H), 3.25-3.30 (m, 1H), 3.64 (t, 2H, J=5.9 Hz), 6.51 (d, 2H, J=8.3Hz), 6.96 (d, 2H, J=8.3 Hz).

EXAMPLE 67N-[1-[2-[1-(2-Hydroxyethyl)cyclobutyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution of2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclobutyl]eth-anol(synthesized in Example 66) (175 mg) in tetrahydrofuran (3 mL) was addedtriethylamine (0.46 mL) and 2-furoyl chloride (0.16 mL) successively.The solution was stirred at room temperature for 40 minutes. To thereaction solution were added methanol (4 mL) and a 3N aqueous potassiumhydroxide solution (2 mL). The solution was stirred for additional 30minutes. Saturated sodium chloride solution was added to the reactionsolution and it was extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresulting residue was purified by chromatography [NH silica gel,hexane-ethyl acetate (1:1)] to give the title compound (159 mg).

¹H-NMR (CDCl₃) δ: 1.46-1.86 (m, 14H), 2.09-2.16 (m, 2H), 2.22-2.26 (m,2H), 2.39 (s, 3H), 2.96-3.02 (m, 2H), 3.55 (t, 2H, J=6.8 Hz), 4.10 (brs,1H), 4.71-4.78 (m, 1H), 5.37 (brs, 1H), 6.13 (dd, 1H, J=2.0 Hz, 3.5 Hz),7.01 (d, 2H, J=8.3 Hz), 7.19 (d, 2H, J=8.3 Hz), 7.34 (brs, 1H).

EXAMPLE 68 Ethyl Cyclooctylideneacetate

To an ice-cooled suspension of 60% sodium hydride (0.88 g) intetrahydrofuran (40 mL) was added triethyl phosphonoacetate (4.8 mL)dropwise over 5 minutes. After stirring the suspension under ice coolingfor 1 hour, cyclooctanone (2.52 g) was added. The suspension was stirredunder ice cooling for additional 1 hour and then at room temperature for87 hours. The reaction solution was poured into saturated aqueousammonium chloride solution and it was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The resulting residue was purified by chromatography[silica gel, hexane-isopropyl ether (97:3)] to give the title compound(2.67 g).

¹H-NMR (CDCl₃): 1.27 (t, 3H, J=7.0 Hz), 1.40-1.56 (m, 6H), 1.71-1.84 (m,4H), 2.29-2.33 (m, 2H), 2.73-2.77 (m, 2H), 4.13 (q, 2H, J=7.0 Hz), 5.72(s, 1H).

EXAMPLE 69 2-Cyclooctylidenethyl acetate

To an ice-cooled solution of ethyl cyclooctylideneacetate (4.82 g) intetrahydrofuran (25 mL) was added 1M diisobutylaluminum hydride/hexane(73.8 mL) dropwise over 15 minutes. After stirring the reaction solutionunder ice cooling for 30 minutes, 2N hydrochloric acid (50 mL) wasadded. After allowing the solution for its temperature rise to roomtemperature, it was stirred for additional 30 minutes. The reactionsolution was extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and dried over under reduced pressure. Tothe resulting residue were added pyridine (22 mL), acetic anhydride(10.1 mL) and N,N-dimethylaminopyridine (0.26 g) successively. Thesolution was stirred at room temperature for 18 hours. The reactionsolution was diluted with ethyl acetate, washed in turn with 2Nhydrochloric acid, saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution. The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The resulting residue was purified by chromatography [silica gel,hexane-ethyl acetate (97:3)] to give the title compound (3.41 g).

¹H-NMR (CDCl₃): 1.45-1.56 (m, 6H), 1.58-1.70 (m, 4H), 2.06 (s, 3H),2.18-2.23 (m, 2H), 2.23-2.28 (m, 2H), 4.60 (d, 2H, J=7.0 Hz), 5.37 (t,1H, J=7.0 Hz).

EXAMPLE 70 Methyl (1-vinylcyclooctyl)acetate

To an ice-cooled solution of diisopropylamine (1.68 mL) intetrahydrofuran (10 mL) was added 1.57 M n-butyllithium/hexane (7.0 mL)dropwise over 10 minutes. After stirring the reaction solution under icecooling for additional 30 minutes, it was cooled to −78° C. and asolution of 2-cyclobutylidene ethyl acetate (1.96 g) in tetrahydrofuran(2 mL) was added thereto dropwise over 10 minutes. After stirring thereaction solution at that temperature for 1 hour, chlorotrimethylsilane(1.52 mL) was added dropwise over 5 minutes. The reaction solution wasstirred at room temperature for 1 hour, and then, heated under refluxfor 4.5 hours. The reaction solution was ice-cooled and methanol (5 mL)and a 3N aqueous sodium hydroxide solution (8 ml) were added. Thesolution was stirred for 30 minutes. Then, conc. hydrochloric acid (4mL) was added to the solution and it was stirred for additional 30minutes. The reaction solution was extracted with chloroform. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The resulting residue was dissolved inN,N-dimethylformamide (20 mL), to which potassium carbonate (8.29 g) andmethyl iodide (1.87 mL) were added. The solution was stirred at roomtemperature for 3 hours. The reaction solution was filtered with Celiteand insolubles on Celite were washed with ethyl acetate. The filtratewas combined with the wash and washed in turn with 2N hydrochloric acidand saturated aqueous sodium chloride solution. The organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The resulting residue was purified by chromatography [silicagel, hexane-ethyl acetate (97:3)] to give the title compound (1.33 g).

¹H-NMR (CDCl₃): 1.45-1.73 (m, 14H), 2.31 (s, 2H), 3.61 (s, 3H), 4.96 (d,1H, J=17.5 Hz), 5.04 (d, 1H, J=10.5 Hz), 5.77 (dd, 1H, J=10.5 Hz, 17.5Hz).

EXAMPLE 71 3-Oxaspiro[5.7]tridecan-2-one

To an ice-cooled solution of methyl (1-vinylcyclooctyl)acetate (1.33 g)in tetrahydrofuran (6 mL) was added 0.5M9-borabicyclo[3.3.1]nonane/tetrahydrofuran (25.3 mL) dropwise over 15minutes. The reaction solution was then allowed for its temperature torise to room temperature and it was stirred for additional 2 hours. Thereaction solution was again ice-cooled, and ethanol (8 mL), a 6N aqueoussodium hydroxide solution (11 mL) and 30% hydrogen peroxide (11 mL) weresuccessively to the solution. The reaction solution was allowed for itstemperature to rise to room temperature and it was stirred foradditional 75 minutes. The reaction solution was again ice-cooled. Afteraddition of conc. hydrochloric acid (8 mL), the solution was stirred foradditional 30 minutes. The reaction solution was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride solution, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The resulting residue was purified bychromatography [silica gel, hexane-ethyl acetate (9:1)] to give thetitle compound (0.74 g).

¹H-NMR (CDCl₃) δ: 1.49-1.63 (m, 14H), 1.71 (t, 2H, J=6.0 Hz), 2.32 (s,2H), 4.32 (t, 2H, J=6.0 Hz).

EXAMPLE 72 3-Oxaspiro[5.7]tridecan-2-ol

To a solution of 3-oxaspiro[5.7]tridecan-2-one (0.74 g) intetrahydrofuran (9 mL) cooled at −78° C. was added 1M diisobutylaluminumhydride/tetrahydrofuran (4.9 mL) dropwise over 5 minutes. The reactionsolution was then stirred at that temperature for 30 minutes. Water(0.18 mL) was added to the reaction solution. After allowing thetemperature to rise to room temperature, a 15% aqueous sodium hydroxidesolution (0.18 mL) and water (0.54 mL) were successively added to thesolution. After stirring the reaction solution at room temperature for10 minutes, diethyl ether (9 mL) and anhydrous magnesium sulfate (0.17g) were added, and the solution was stirred for additional 15 minutes.The reaction solution was filtered with Celite. The filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby chromatography [silica gel, hexane-ethyl acetate (3:1 to 2:1 to 1:1)]to give the title compound (0.62 g).

¹H-NMR (CDCl₃) δ: 1.17 (dd, 1H, J=8.0 Hz, 13.0 Hz), 1.35-1.61 (m, 16H),1.76 (d, 1H, J=13.0 Hz), 2.80 (brt, 1H, J=5.5 Hz), 3.66 (ddd, 1H, J=4.0Hz, 9.5 Hz, 13.5 Hz), 3.89 (ddd, 1H, J=4.0 Hz, 4.0 Hz, 11.5 Hz), 4.93(ddd, 1H, J=3.0 Hz, 5.5 Hz, 8.0 Hz).

EXAMPLE 732-[1-[2-[4-(p-Toluidino)piperidin-1-yl]ethyl]cyclooctyl]eth-anol

To a suspension of 4-(p-toluidino)piperidine ditrifluoroacetate(synthesized in Preparation Example 4-5) (1.31 g) in 1,2-dichloroethane(6 mL) was added triethylamine (0.96 mL). The suspension was stirred atroom temperature for 5 minutes. Then, a solution of3-oxaspiro[5.7]tridecan-2-ol (synthesized in Example 72) (0.62 g) in1,2-dichloroethane (3 mL) was added to the suspension, and it wasstirred at room temperature for additional 10 minutes. The reactionsolution was ice-cooled and sodium triacetoxyborohydride (0.70 g) wasadded thereto. The reaction solution was then allowed for itstemperature to rise to room temperature, and the solution was stirredfor additional 4.5 hours. Saturated aqueous sodium bicarbonate solutionwas added to the reaction solution and it was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby chromatography [silica gel, methanol-chloroform (3:97 to 1:9)] togive the title compound (0.53 g).

¹H-NMR (CDCl₃) δ: 1.33-1.56 (m, 20H), 2.00-2.09 (m, 2H), 2.09-2.20 (m,2H), 2.22 (s, 3H), 2.34 (t, 2H, J=6.0 Hz), 2.86-3.00 (m, 2H), 3.23-3.34(m, 1H), 3.67 (t, 2H, J=6.0 Hz), 6.51 (d, 2H, J=8.0 Hz), 6.97 (d, 2H,J=8.0 Hz).

EXAMPLE 74N-[1-[2-[1-(2-Hydroxyethyl)cyclooctyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution of2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclooctyl]eth-anol(synthesized in Example 73) (0.53 g) in tetrahydrofuran (7 mL) wereadded triethylamine (0.79 mL) and 2-furoyl chloride (0.35 mL)successively. The solution was stirred at room temperature for 1 hour.To the reaction solution was added methanol (7 mL) and a 3N aqueouspotassium hydroxide solution (4.7 mL), and it was stirred at roomtemperature for 15 hours. Water was added to the reaction solution andit was extracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The resulting residuewas purified by chromatography [silica gel, methanol-chloroform (5:95)]to give the title compound (0.55 g).

¹H-NMR (CDCl₃) δ: 1.30-1.55 (m, 20H), 1.81-1.89 (m, 2H), 2.07-2.16 (m,2H), 2.23-2.29 (m, 2H), 2.40 (s, 3H), 2.94-3.02 (m, 2H), 3.59 (t, 2H,J=6.5 Hz), 4.76 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.32 (brs, 1H), 6.13 (dd,1H, J=1.5 Hz, 3.0 Hz), 7.00 (d, 2H, J=8.0 Hz), 7.18 (d, 2H, J=8.0 Hz),7.35 (brs, 1H).

EXAMPLE 75 Ethyl (tetrahydropyran-4-ylidene)acetate

To an ice-cooled suspension of 60% sodium hydride (0.72 g) inN,N-dimethylformamide (30 mL) was added triethyl phosphonoacetate (3.6mL) dropwise over 5 minutes. After stirring the suspension under icecooling for 45 minutes, tetrahydro-4H-pyran-4-one (1.4 mL) was added tothe suspension dropwise over 3 minutes. The suspension was stirred underice cooling for additional 35 minutes. The reaction solution was pouredinto saturated aqueous ammonium chloride solution and it was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give the title compound (3.31 g).This product was subjected to the subsequent step without furtherpurification.

¹H-NMR (CDCl₃) δ: 1.28 (t, 3H, J=7.3 Hz), 2.32 (t, 3H, J=5.6 Hz), 3.01(t, 2H, J=5.6 Hz), 3.73 (t, 2H, J=5.6 Hz), 3.77 (t, 2H, J=5.6 Hz), 4.15(q, 2H, J=7.3 Hz), 5.68 (s, 1H).

EXAMPLE 76 2-(Tetrahydropyran-4-ylidene)ethyl acetate

To an ice-cooled solution of ethyl (tetrahydropyran-4-ylidene)acetate(3.31 g) in tetrahydrofuran (20 mL) under ice cooling was added 1Mdiisobutylaluminum hydride/hexane (20 mL) dropwise over 25 minutes.After stirring the reaction solution under ice cooling for 1 hour, 1Nhydrochloric acid (100 mL) was added thereto. The temperature wasallowed to rise to room temperature, and the solution was stirred foradditional 30 minutes. The reaction solution was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate anddried under reduced pressure. To the resulting residue were addedpyridine (3 mL), acetic anhydride (3 mL) and N,N-dimethylaminopyridine(0.18 g) successively. The solution was stirred at room temperature for19 hours. The reaction solution was diluted with ethyl acetate, washedin turn with 1N hydrochloric acid, saturated aqueous sodium bicarbonatesolution and saturated aqueous sodium chloride solution. The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The resulting residue was purified by chromatography[silica gel, hexane-ethyl acetate (20:1 to 7:3)] to give the titlecompound (2.50 g).

¹H-NMR (CDCl₃) δ: 2.06 (s, 3H), 2.22-2.27 (m, 2H), 2.34-2.37 (m, 2H),3.66-3.72 (m, 4H), 4.59 (d, 2H, J=7.3 Hz), 5.38-5.42 (m, 1H).

EXAMPLE 77 Methyl (4-vinyltetrahydropyran-4-yl)acetate

To an ice-cooled solution of diiospropylamine (1.00 mL) intetrahydrofuran (10 mL) was added 1.57 M n-butyllithium/hexane (4.17 mL)dropwise over 5 minutes. After stirring the reaction solution under icecooling for additional 30 minutes, it was cooled to −78° C., to which asolution of acetic acid 2-(tetrahydropyran-4-ylidene)ethyl (1.00 g)ester in tetrahydrofuran (1 mL) was added dropwise over 5 minutes. Afterstirring the reaction solution at that temperature for 80 minutes,chlorotrimethylsilane (0.90 mL) was added thereto dropwise over 5minutes. The reaction solution was stirred at room temperature for 1hour, and then, heated under reflux for 4.5 hours. The reaction solutionwas ice-cooled and methanol (3 mL) and a 3N aqueous sodium hydroxidesolution (5 ml) were added thereto. The solution was stirred for 15minutes. Then, conc. hydrochloric acid (2 mL) was added to the solutionand the solution was stirred for additional 5 minutes. The reactionsolution was extracted with chloroform. The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresulting residue (1.27 g) was dissolved in N,N-dimethylformamide (10mL), to which potassium carbonate (1.38 g) and methyl iodide (0.37 mL)were added. The reaction solution was stirred at room temperature for1.5 hours. The reaction solution was poured into saturated aqueousammonium chloride solution and it was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloridesolution, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The resulting residue was purified by chromatography[silica gel, hexane-ethyl acetate (9:1 to 7:3)] to give the titlecompound (455 mg).

¹H-NMR (CDCl₃) δ: 1.68-1.80 (m, 4H), 2.39 (s, 2H), 3.58-3.64 (m, 2H),3.63 (s, 3H), 3.71-3.76 (m, 2H), 5.05 (d, 1H, J=17.6 Hz), 5.23 (d, 1H,J=11.2 Hz), 5.79 (dd, 1H, J=11.2 Hz, 17.6 Hz).

EXAMPLE 78 3,9-Dioxaspiro[5.5]undecan-2-one

To an ice-cooled solution of methyl (4-vinyltetrahydropyran-4-yl)acetate(455 mg) in tetrahydrofuran (3 mL) was added 0.5M9-borabicyclo[3.3.1]-nonane/tetrahydrofuran (10.0 mL) dropwise over 10minutes. The reaction solution was allowed for its temperature to riseto room temperature and it was stirred for additional 17 hours. Thereaction solution was again ice-cooled and ethanol (2 mL), a 6N aqueoussodium hydroxide solution (4 mL) and 30% hydrogen peroxide (4 mL) wereadded thereto successively. The reaction solution was then allowed forits temperature to rise to room temperature and it was stirred foradditional 30 minutes. The reaction solution was again ice-cooled. Afteraddition of conc. hydrochloric acid (2.5 mL), the reaction solution wasallowed for its temperature to rise to room temperature. The solutionwas stirred for additional 1 hour. The reaction solution was extractedwith chloroform. The organic layer was washed with saturated aqueoussodium chloride solution, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby chromatography [silica gel, hexane-ethyl acetate (7:3 to 6:4)] togive the title compound (271 mg).

¹H-NMR (CDCl₃) δ: 1.57 (t, 4H, J=5.4 Hz), 1.82-1.86 (m, 2H), 2.48 (s,3H), 3.64-3.74 (m, 4H), 4.34-4.37 (m, 2H).

EXAMPLE 79 3,9-Dioaxaspiro[5.5]undecan-2-ol

To a solution of 3,9-dioxaspiro[5.5]undecan-2-one (134 mg) intetrahydrofuran (2 mL) cooled at −78° C. was added 1M diisobutylaluminumhydride/tetrahydrofuran (1.0 mL) dropwise over 5 minutes. The reactionsolution was then stirred at that temperature for 1 hour. Water (40 μL)was added to the reaction solution. After allowing the solution for itstemperature to rise to room temperature, a 15% aqueous sodium hydroxidesolution (40 μL) and water (120 μL) were added successively. Afterstirring the solution at room temperature for 15 minutes, diethyl ether(2 mL) and anhydrous magnesium sulfate (0.17 g) were added thereto. Thesolution was stirred for additional 30 minutes. The reaction solutionwas filtered with Celite. The filtrate was concentrated under reducedpressure to give the title compound (136 mg). This product was subjectedto the subsequent step without further purification.

¹H-NMR (CDCl₃) δ: 1.41 (dd, 1H, J=6.8 Hz, 13.2 Hz), 1.48-1.68 (m, 6H),1.80 (dd, 1H, J=1.5 Hz, 13.2 Hz), 3.45 (brs, 1H), 3.61-3.73 (m, 5H),3.93-3.99 (m, 1H), 5.01 (dd, 1H, J=2.4 Hz, 6.8 Hz).

EXAMPLE 802-[1-[2-[4-(p-Toluidino)piperidin-1-yl]ethyl]tetrahydropyran-4-yl]ethanol

To a suspension of 4-(p-toluidino)piperidine trifluoroacetate(synthesized in Preparation Example 4-5) (656 mg) in tetrahydrofuran (5mL) was added triethylamine (0.44 mL). The solution was stirred at roomtemperature for 25 minutes. Then, 3,9-dioxaspiro[5.5]undecan-2-ol(synthesized in Example 79) (135 mg) in tetrahydrofuran (3 mL) was addedto the solution and it was stirred at room temperature for additional 5minutes. The reaction solution was ice-cooled and sodiumtriacetoxyborohydride (333 mg) was added thereto. After allowing thereaction solution for its temperature rise to room temperature, it wasstirred for additional 26 hours. To the reaction solution was added a 3Naqueous sodium hydroxide solution (10 mL) and it was extracted withethyl acetate.

The organic layer was washed with saturated aqueous sodium chloridesolution, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The resulting residue was purified by chromatography[silica gel, chloroform-methanol (20:1)] to give the title compound (240mg).

¹H-NMR (CDCl₃) δ: 1.41-1.53 (m, 6H), 1.67-1.70 (m, 4H), 2.05 (d, 2H,J=11.7 Hz), 2.11-2.17 (m, 2H), 2.22 (s, 3H), 2.34 (t, 2H, J=6.3 Hz),2.91 (d, 2H, J=11.2 Hz), 3.25-3.31 (m, 1H), 3.61-3.71 (m, 6H), 6.50 (d,2H, J=8.3 Hz), 6.96 (d, 2H, J=8.3 Hz).

EXAMPLE 81N-[1-[2-[4-(2-Hydroxyethyl)tetrahydropyran-4-yl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution of2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]tetrahydropyran-4-yl]ethanol(synthesized in Example 80) (239 mg) in tetrahydrofuran (3 mL) was addedtriethylamine (0.29 mL) and 2-furoyl chloride (0.17 mL) successively.The reaction solution was stirred at room temperature for 30 minutes. Tothe reaction solution were added methanol (4 mL) and a 3N aqueouspotassium hydroxide solution (2 mL). The reaction solution was stirredat room temperature for additional 15 minutes. Water was added to thereaction solution and it was extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium chloride solution, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The resulting residue was purified by chromatography [silica gel,chloroform-methanol (30:1)] to give the title compound (210 mg).

¹H-NMR (CDCl₃) δ: 1.35-1.45 (m, 6H), 1.49 (dd, 2H, J=3.4 Hz, 12.2 Hz),1.56 (t, 2H, J=6.8 Hz), 1.64 (t, 2H, J=6.8 Hz), 1.86 (brd, 2H, J=12.7Hz), 2.14 (t, 2H, J=12.2 Hz), 2.29 (t, 2H, J=7.3 Hz), 2.40 (s, 3H), 2.98(brd, 2H, J=11.7 Hz), 3.61-3.64 (m, 6H), 4.71-4.79 (m, 1H), 5.34 (brs,1H), 6.13 (dd, 1H, J=1.5 Hz, 3.4 Hz), 7.00 (d, 2H, J=8.3 Hz), 7.19 (d,2H, J=8.3 Hz), 7.34 (s, 1H).

EXAMPLE 82 Diethyl 1-benzylpiperidine-4,4-diacetate

To ice-cooled 7M ammonia/methanol (28 mL) were added1-benzyl-4-piperidone (9.27 mL) and ethyl cyanoacetate (10.6 mL). Thesolution was allowed to stand in a refrigerator (0° C.) for 5 days. Thecrystals thus separated out were recovered by filtration (9.14 g).

Water (8.81 mL) and conc. sulfuric acid (10.3 mL) were added to theresulting crystals (8.64 g). The mixture was heated in an oil bath at100° C. for 2 days. After the temperature was allowed to rise to roomtemperature, ethanol (100 mL) was added to the mixture and it wasconcentrated by an evaporator to azeotropically distill water. Thisprocedure was repeated four times. Ethanol (73 mL) was added to theproduct and the solution was heated under reflux for 24 hours. After icecooling, sodium carbonate (20 g) was added to the solution and it wasconcentrated under reduced pressure. Ethyl acetate was added to thereaction solution and the solution was washed in turn with water andsaturated aqueous sodium chloride solution. The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The resulting residue was purified by chromatography [silica gel,methanol-chloroform (3:97)] to give the title compound (6.25 g).

¹H-NMR (CDCl₃): 1.24 (t, 6H, J=6.5 Hz), 1.68 (brt, 4H, J=5.5 Hz), 2.44(brt, 4H, J=5.5 Hz), 2.56 (s, 4H), 3.50 (s, 2H), 4.11 (q, 4H, J=6.5 Hz),7.21-7.32 (m, 5H).

EXAMPLE 83 1-Benzyl-4,4-bis(2-hydroxyethyl)piperidine

To an ice-cooled solution of lithium aluminum hydride (0.76 g) intetrahydrofuran (120 mL) was added a solution of diethyl1-benzylpiperidine-4,4-diacetate (3.47 g) in tetrahydrofuran (10 mL)dropwise. The ice bath was removed and the reaction solution was stirredat room temperature for 1 hour. The reaction solution was againice-cooled, to which water (0.76 mL), a 15% aqueous sodium hydroxidesolution (0.76 mL) and water (2.28 mL) were added successively. Thesubstance thus separated out was filtered off with Celite. The filtratewas concentrated under reduced pressure to give the title compound (ca.2.63 g). This product was subjected to the subsequent step withoutfurther purification.

¹H-NMR (CDCl₃) δ: 1.51 (brt, 4H, J=5.0 Hz), 1.68 (t, 4H, J=6.5 Hz), 2.42(brt, 4H, J=5.0 Hz), 3.51 (s, 2H), 3.72 (t, 4H, J=6.5 Hz), 7.22-7.35 (m,5H).

EXAMPLE 842-[1-Benzyl-[4-[2-(tert-butyldiphenylsiloxy)ethyl]piperidin-4-yl]ethanol

To a solution of 1-benzyl-4,4-bis(2-hydroxyethyl)piperidine (ca. 2.63 g)in dichloromethane (50 mL) were added triethylamine (1.81 mL) and teri-butyldiphenylchlorosilane (2.86 mL). The reaction solution was stirredat room temperature for 18 hours. Chloroform was added to the reactionsolution, and the solution was washed with saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution. Thesolution was dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The resulting residue was purified bychromatography [silica gel, methanol-chloroform (3:97)] to give thetitle compound (2.61 g).

¹H-NMR (CDCl₃) δ: 1.04 (s, 9H), 1.43 (brt, 4H, J=5.5 Hz), 1.57 (t, 2H,J=7.5 Hz), 1.64 (t, 2H, J=7.0 Hz), 2.27-2.42 (m, 4H), 3.46 (s, 2H), 3.57(t, 2H, J=7.5 Hz), 3.70 (t, 2H, J=7.0 Hz), 7.20-7.31 (m, 5H), 7.36-7.46(m, 6H), 7.65-7.69 (m, 4H).

EXAMPLE 85[1-Benzyl-4-[2-(tert-butyldiphenylsiloxy)ethyl]piperidin-4-yl]acetaldehyde

To a solution of oxalyl chloride (0.26 mL) in dichloromethane (3 mL)cooled at −78° C. was added a solution of dimethyl sulfoxide (0.43 mL)in dichloromethane (1 mL) dropwise over 10 minutes. The reactionsolution was stirred at −78° C. for 30 minutes. To the reaction solutionwas added a solution of2-[1-benzyl-[4-[2-(tert-butyldiphenylsiloxy)ethyl]piperidin-4-yl]ethanol(0.75 g) in dichloromethane (2 mL) dropwise over 10 minutes. Thesolution was stirred at −78° C. for 30 minutes. Triethylamine (2.1 mL)was added to the solution and it was stirred for 10 minutes. Afterallowing the temperature to rise to room temperature, the solution wasstirred for 30 minutes.

Dichloromethane was added to the solution and it was washed withsaturated aqueous sodium bicarbonate solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give thetitle compound (0.75 g). This product was subjected to the subsequentstep without further purification.

¹H-NMR (CDCl₃) δ: 1.03 (s, 9H), 1.54-1.61 (m, 6H), 1.79 (t, 2H, J=6.5Hz), 2.34-2.44 (m, 4H), 3.47 (s, 2H), 3.75 (t, 2H, J=6.5 Hz), 7.22-7.33(m, 5H), 7.36-7.46 (m, 6H), 7.63-7.67 (m, 4H), 9.78 (t, 1H, J=2.5 Hz).

EXAMPLE 861-[2-[1-Benzyl-4-[2-(tert-butyldiphenylsiloxy)ethyl]piperidin-4-yl]ethyl]-4-toluidinopiperidine

To a suspension of 4-(p-toluidino)piperidine ditrifluoroacetate(synthesized in Preparation Example 4-5) (0.63 g) in 1,2-dichloroethane(3 mL) was added triethylamine (0.42 mL). The suspension was stirred atroom temperature for 25 minutes. Then, to the suspension was added[1-benzyl-4-[2-(tert-butyldiphenylsiloxy)ethyl]piperidin-4-yl]acetaldehyde(synthesized in Example 85) (0.75 g) in 1,2-dichloroethane (1.5 mL), andit was stirred at room temperature for additional 5 minutes. Thereaction solution was ice-cooled, to which sodium triacetoxyborohydride(0.50 g) was added. After allowing the temperature to rise to roomtemperature, the solution was stirred for additional 15 hours. Saturatedaqueous sodium bicarbonate solution was and it was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby chromatography [NH silica gel, ethyl acetate-chloroform (5:95)] togive the title compound (0.87 g).

¹H-NMR (CDCl₃) δ: 1.03 (s, 9H), 1.34-1.47 (m, 6H), 1.62 (t, 2H, J=7.0Hz), 1.65-1.76 (m, 2H), 1.90-2.03 (m, 4H), 2.15-2.21 (m, 2H), 2.23 (s,3H), 2.27-2.40 (m, 4H), 2.68-2.79 (m, 2H), 3.17-3.27 (m, 1H), 3.46 (s,2H), 3.68 (t, 2H, J=7.0 Hz), 6.52 (d, 2H, J=8.0 Hz), 6.98 (d, 2H, J=8.0Hz), 7.21-7.33 (m, 5H), 7.35-7.45 (m, 6H), 7.64-7.69 (m, 4H).

EXAMPLE 87N-[1-[2-[1-Benzyl-4-[2-(tert-butyldiphenylsiloxy)ethyl]pipe-ridin-4-yl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution of1-[2-[1-benzyl-4-[2-(tert-butyldiphenylsiloxy)ethyl]piperidin-4-yl]ethyl]-4-toluidinopiperidine(synthesized in Example 86) (0.87 g) in tetrahydrofuran (7 mL) was addedtriethylamine (0.35 mL) and 2-furoyl chloride (0.19 mL) successively.The reaction solution was stirred at room temperature for 1 hour.Saturated aqueous sodium bicarbonate solution was added to the solutionand it was extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingresidue was purified by chromatography [silica gel, chloroform-methanol(95:5)] to give the title compound (0.73 g).

¹H-NMR (CDCl₃) δ: 1.02 (s, 9H), 1.27-1.51 (m, 6H), 1.58 (t, 2H, J=7.5Hz), 1.63-1.74 (m, 2H), 1.75-1.83 (m, 2H), 1.88-1.97 (m, 2H), 2.08-2.15(m, 2H), 2.26-2.36 (m, 4H), 2.39 (s, 3H), 2.77-2.84 (m, 2H), 3.45 (s,2H), 3.64 (t, 2H, J=7.0 Hz), 4.73 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.35(brs, 1H), 6.14 (dd, 1H, J=2.0 Hz, 3.5 Hz), 7.00 (d, 2H, J=8.0 Hz), 7.17(d, 2H, J=8.0 Hz), 7.20-7.32 (m, 5H), 7.34-7.47 (m, 7H), 7.63-7.67 (m,4H).

EXAMPLE 88N-[1-[2-[1-Benzyl-4-(2-hydroxyethyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide

To a solution of N-[1-[2-1-benzyl-4-[2-(tert-butyldiphenylsiloxy)ethyl]piperidin-4-yl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide(synthesized in Example 87) (0.73 g) in tetrahydrofuran (3 mL) was added1M tetra n-butylammonium fluoride/tetrahydrofuran (1.9 mL). The reactionsolution was stirred at room temperature for 15 hours. Saturated aqueoussodium bicarbonate solution was added to the solution and it wasextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingresidue was purified by chromatography [NH silica gel,chloroform-methanol (98:2)] to give the title compound (0.32 g).

¹H-NMR (CDCl₃) δ: 1.38-1.51 (m, 8H), 1.56 (t, 2H, J=6.5 Hz), 1.81-1.89(m, 2H), 2.07-2.16 (m, 2H), 2.26 (t, 2H, J=7.0 Hz), 2.33-2.40 (m, 4H),2.40 (s, 3H), 2.94-3.00 (m, 2H), 3.48 (s, 2H), 3.60 (t, 2H, J=6.5 Hz),4.75 (tt, 1H, J=4.0 Hz, 12.0 Hz), 5.32 (brs, 1H), 6.13 (dd, 1H, J=2.0Hz, 3.0 Hz), 7.00 (d, 2H, J=8.0 Hz), 7.18 (d, 2H, J=8.0 Hz), 7.21-7.32(m, 5H), 7.35 (d, 1H, J=1.0 Hz).

INDUSTRIAL APPLICABILITY

The novel 4-(2-furoyl)aminopiperidine derivatives obtained according tothis invention possess opioid μ antagonistic activity and are effectivefor the treatment or prevention of side effects (which are caused by μreceptor agonists) selected from constipation, nausea and emesis oritching, or idiopathic constipation, postoperative ileus, paralyticileus, irritable bowel syndrome or chronic itching.

1. A compound represented the general formula (V):

wherein X is CH or N; and Y_(a) is a group of the general formula (VI)

or a group of the general formula (VI-a):

or a group of the general formula (VII):

or a group of the general formula (VIII):

wherein a, b and c are each an integer of 0-6; Z is CH₂ or NH; W is O orS; T is O or N—R¹⁵ wherein R¹⁵ is H, C1-C6 alkyl group, a benzyl groupor a phenethyl group; R⁹ is H, a C1-C6 alkoxycarbonyl group, abenzyloxy-carbonyl group, a carboxy group, a 2-phenyl-1,3-dioxan-5-ylgroup, a 2,2-dimethyl-1,3-dioxan-5-yl group or a group of the generalformula (IX); and R¹⁰ is H or a group of the general formula (IX):

wherein d is an integer of 0-6; and R¹¹, R¹², and R¹³ may be the same ordifferent and are each independently H or —(CH₂)_(e)R¹⁴ wherein e is0-6, and R¹⁴ is a C1-C6 alkanoyloxy group, a benzoyloxy group, a2-furoyloxy group, a C1-C6 alkoxy C1-C6 alkoxy group, a di C1-C6alkanoyloxy C1-C6 alkylphenoxy group, a C1-C6 alkyldiarylsiloxy group, aC1-C6 alkoxycarbamoyl group, a carboxy group, a C1-C6 alkoxycarbonylgroup, a benzyloxycarbonyl group, a cyano group, a C1-C6alkylsulfonamido group, a C1-C6 alkoxycarbonylphenoxy group or a diC1-C6 alkoxycarbonylphenoxy group.